Nonrenal Neoplasms Research Articles

LITESPARK-004 (MK-6482-004) phase 2 study of belzutifan, an oral hypoxia-inducible factor 2α inhibitor (HIF-2α), for von Hippel-Lindau (VHL) disease: Update with more than two years of follow-up data.

4546 Background: VHL disease is associated with malignant or benign tumors, including renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and hemangioblastomas. Alterations in the VHL gene cause aberrant stabilization and accumulation of HIF-2α, leading to activation of genes associated with tumor growth. Antitumor activity observed in the ongoing open-label phase 2 study, LITESPARK-004 (NCT03401788), led to the approval of belzutifan for the treatment of patients (pts) with VHL disease who require therapy for associated RCC, CNS hemangioblastomas, or pNETs not requiring immediate surgery. Updated results are presented after > 2 years of follow-up. Methods: Pts (≥18 years) with germline VHL alterations, ≥1 measurable nonmetastatic RCC tumor, no tumor of > 3 cm that necessitated immediate surgery, no prior anticancer systemic treatment, and an ECOG PS score of 0 or 1 received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or pt withdrawal. The primary end point was objective response rate (ORR) in VHL disease–associated RCC per RECIST v1.1 by independent central review (ICR). Secondary end points were safety, ORR in non-RCC neoplasms, and duration of response (DOR) in renal and nonrenal neoplasms, per RECIST v1.1 by ICR. Results: Of 61 pts, 50 were on treatment as of July 15, 2021; the primary reasons for discontinuation were disease progression in RCC neoplasms (n = 4) and pt decision to withdraw (n = 4). Twenty pts (33%) had ≥1 pNET and 50 (82%) had ≥1 CNS hemangioblastoma evaluable by ICR at baseline. At baseline, 97% of pts (n = 59) had prior VHL-related surgery; 38 pts had ≥1 VHL-related surgery within 3 years before starting belzutifan. Median time from first dose to database cutoff date was 29.3 mo (range, 27.6-37.5). ORR in RCC was 59% (n = 36), with 2 CRs (3%) and 34 PRs (56%). Median DOR was not reached (range, 8.3+ to 27.6+ mo). ORR in CNS hemangioblastomas was 38% (n = 19; 3 CRs; 16 PRs); median DOR was not reached (range, 3.7+ to 28.0+ mo). ORR in pNETS was 90% (n = 18; 3 CRs; 15 PRs); median DOR was not reached (range, 11.0+ to 31.0+ mo). Three pts (5%) underwent VHL-related surgeries after starting belzutifan. Grade 3 treatment-related adverse events (TRAEs) were reported in 10 pts (16%); the most common was anemia (n = 6 [10%]). No pt had a grade 4 or 5 TRAE. Two pts (3%) stopped treatment because of TRAEs (grade 1 dizziness and grade 2 intracranial hemorrhage). Conclusions: After a median follow-up of 29.3 mo, belzutifan continued to show antitumor activity in VHL disease–related neoplasms, including RCC, pNETs, and CNS hemangioblastomas, whereas the safety profile remained consistent with that of previous reports. These results support the use of belzutifan as a systemic treatment for VHL disease. Clinical trial information: NCT03401788.

Tissue-Based Immunohistochemical Markers for Diagnosis and Classification of Renal Cell Carcinoma

The development and description of renal cell carcinoma (RCC) subtypes has led to an increase in demand for tissue biomarkers. This has implications not only in informing diagnosis, but also in guiding treatment selection and in prognostication. Although historically, many immunohistochemical (IHC) stains have been widely characterized for RCC subtypes, challenges may arise in interpreting these results. These may include variations in tumor classification, specimen collection and processing, and IHC techniques. In light of the reclassification of RCC subtypes in 2016, there remains a requirement for a comprehensive outline of tissue biomarkers that may be used to differentiate between RCC subtypes and distinguish these from other non-renal neoplasms. In this review, concise summaries of the commonest RCC subtypes, including clear cell, papillary, and chromophobe RCC, have been provided. Important differences have been highlighted between chromophobe RCC and renal oncocytomas. An overview of the current landscape of tissue biomarkers in other RCC subtypes has also been explored, revealing the variable staining results reported for some markers, whilst highlighting the essential markers for diagnosis in other subtypes.

Analyzing renal involvement in 100 cases of hematological malignancy

Background: Hematological malignancies are the most common nonrenal neoplasms affecting the kidneys. The incidence and type of renal involvement in these malignancies are variable and differ according to malignancy. Objective: To study the prevalence of renal involvement in hematological malignancies and to study the clinical profile of patients in various malignancies. Materials and Methods: A total of 100 consecutive patients of hematological malignancies (leukemia, lymphoma, and multiple myeloma) were prospectively studied for renal involvement and clinical profile. Results: There were 72 men and 28 women with mean age of 46.85 ± 19.23 years. Among them, 43% patients had leukemia, 33% patients had lymphoma, and 24% patients had multiple myeloma. Renal failure was present in 37% of the total patients and one-third patients were having azotemic symptoms at presentation. Mean blood urea and serum creatinine levels were 73.75 ± 77.49 and 2.42 ± 3.22 mg/dl, respectively. Mean glomerular filtration rate (GFR) was 71.29 ± 54.92 ml/min and 17% patients had GFR < 15 ml/min; 62.5% patients of multiple myeloma had renal failure. Four patients had acute urate nephropathy (three patients had acute leukemia and one patient had multiple myeloma). Of the total, 18% patients had hypercalcemia and 41.7% patients had myeloma. Hyperuricemia was observed in 55.5% patients. Tumor lysis syndrome was seen in three patients and all these patients were having multiple myeloma. Male sex, multiple myeloma, and hyperuricemia were significant factors contributing to renal failure (p < 0.05). Conclusion: All patients with hematological malignancies should be evaluated for renal dysfunction and all preventive measures should be used in these patients, especially when initiated on chemotherapy.

Renal Cell Carcinoma with Rhabdoid and Sarcomatoid Features Presented as a Metastatic Thigh Mass with an Unusual Immunohistochemical Profile

Renal cell carcinoma (RCC) may metastasize anywhere in the body and sometimes the primary tumor is missing and necessitates extensive investigations to detect. In this report, we describe a case of RCC metastasizing to the thigh in a 70 year old male with a highly pleomorphic morphology suggesting a high grade sarcoma that showed unequivocal positivity for desmin directing the diagnosis for pleomorphic rhabdomyosarcoma. After completion of 33 cycles of radiotherapy, the patient developed large intraabdominal mass that showed conventional areas of RCC with immunoreactivity for CD10, CK, EMA, carbonic anhydrase IX and vimentin. The tumor cells in other areas resembled that of thigh mass which raised suspicions whether the two masses represented the same tumor or not. Surprisingly, the tumor cells of thigh mass showed diffuse positivity for CD10 and focal expression for CK, EMA and carbonic anhydrase IX. Extensive investigations failed to detect any primary renal lesions. The present case demonstrated that RCC can metastasize to virtually any body site and can have significant morphologic overlap with other non-renal neoplasms. Absence of primary origin of RCC according to radiological and operative data should not hinder the diagnosis of metastatic RCC. RCC with sarcomatoid and rhabdoid features carries aggressive behavior manifested by great metastatic potential and short survival time.

PAX-8 Expression in Primary and Metastatic Merkel Cell Carcinoma

PAX-8, a nephric cell lineage transcription factor initially characterized in renal cell carcinomas, is also well recognized as a marker of Müllerian tract and thyroid tumors. From a previous tissue microarray study of nonrenal neoplasms including a variety of skin tumors, we identified PAX-8 staining in a small set of Merkel cell carcinomas, a finding not previously described. Herein, we explore PAX-8 immunoreactivity in 34 whole-section Merkel cell carcinomas (24 primary, 10 metastatic) using polyclonal PAX-8 (prediluted) and 2 varieties of monoclonal PAX-8 (prediluted clone MRQ-50 and 1:100 dilution clone BC12). Nuclear staining intensity and extent was semiquantitatively analyzed with a comparison of staining thresholds required for a "positive" result (≥ 2+ vs. 1+). Thirty-three of 34 (97%) cases showed positive Cell Marque polyclonal PAX-8 staining, whereas 31 of 34 (91%) cases showed positive Cell Marque monoclonal PAX-8 staining. There was no significant difference in staining between primary versus metastatic tumors. The Cell Marque polyclonal PAX-8 was superior to their monoclonal PAX-8, maintaining strong sensitivity using a ≥ 2+ versus 1+ staining cut point for positive results (79% vs. 18%, respectively), which may be important in cases with scant tissue or background staining. The Biocare monoclonal PAX-8 was negative in all cases. PAX-8 staining in Merkel cell carcinoma expands the spectrum of tumors showing immunoreactivity and may prove to be a useful addition to a diagnostic panel. Awareness of this immunoreactivity and recognition of the antibody source and clone are important to preclude diagnostic pitfalls with tumors in the differential diagnosis.

Role of Immunohistochemistry in Diagnosing Renal Neoplasms: When Is It Really Useful?

With the refinement of molecular and histologic classifications of renal neoplasms and the availability of more-effective molecular targeted therapy for specific renal neoplasms, immunohistochemical techniques will play an increasingly important role in the diagnosis of renal neoplasm. During the past few decades, many markers have been evaluated for their role in the diagnosis, prognosis, and prediction of treatment for renal neoplasms. The number of useful markers in our routine practice continues to increase. The challenge will be to choose among them and to decide in which situations immunohistochemistry will be truly useful. To review the diagnostic utility of molecular markers for renal neoplasms and common diagnostic scenarios that call for immunohistochemistry in routine practice. This review is based on published literature and personal experience. Some of the most important and useful markers for the diagnosis of renal neoplasm include cytokeratins, vimentin, PAX2, PAX8, RCC marker, CD10, E-cadherin, kidney-specific cadherin, parvalbumin, claudin-7, claudin-8, α-methylacyl coenzyme A racemase, CD117, TFE3, thrombomodulin, uroplakin III, p63, CD57, and carbonic anhydrase IX. Each marker has its diagnostic role in a specific diagnostic setting. The common diagnostic situations that call for immunohistochemical staining are differential diagnoses of renal versus nonrenal neoplasms, histologic subtyping of renal cell carcinoma, diagnosis of rare primary renal neoplasms, diagnosis of renal neoplasms in small core-biopsy specimens, diagnosis of possible metastatic renal carcinomas, and less frequently, molecular prognostication.

Immunohistochemical Distinction of Primary Adrenal Cortical Lesions From Metastatic Clear Cell Renal Cell Carcinoma

The diagnosis of metastatic clear cell renal cell carcinoma (CC-RCC) can be difficult because of its morphologic heterogeneity and the increasing use of small image-guided biopsies that yield scant diagnostic material. This is further complicated by the degree of morphologic and immunophenotypic overlap with nonrenal neoplasms and tissues, such as adrenal cortex. In this study, a detailed immunoprofile of 63 adrenal cortical lesions, which included 54 cortical neoplasms, was compared with 185 metastatic CC-RCCs using traditional [anticalretinin, CD10, antichromogranin, antiepithelial membrane antigen, anti-inhibin, antimelanA, anticytokeratins (AE1/AE3 and AE1/CAM5.2), antirenal cell carcinoma marker, and antisynaptophysin)] and novel [anticarbonic anhydrase-IX, antihepatocyte nuclear factor-1b, antihuman kidney injury molecule-1 (hKIM-1), anti-PAX-2, anti-PAX-8, antisteroidogenic factor-1 (SF-1), and anti-T-cell immunoglobulin mucin-1] antibodies. Tissue microarray methodology was used to simulate small image-guided biopsies. Staining extent and intensity were scored semiquantitatively for each antibody. In comparing different intensity thresholds required for a "positive" result, a value of ≥2+ was identified as optimal for diagnostic sensitivity/specificity. For the distinction of adrenal cortical lesions from metastatic CC-RCCs, immunoreactivity for the adrenal cortical antigens SF-1 (86% adrenal; 0% CC-RCC), calretinin (89% adrenal; 10% CC-RCC), inhibin (86% adrenal; 9% CC-RCC), and melanA (86% adrenal; 10% CC-RCC) and for the renal epithelial antigens hKIM-1 (0% adrenal; 83% CC-RCC), PAX-8 (0% adrenal; 83% CC-RCC), hepatocyte nuclear factor-1b (0% adrenal; 76% CC-RCC), epithelial membrane antigen (0% adrenal; 78% CC-RCC), and carbonic anhydrase-IX (3% adrenal; 87% CC-RCC) had the most potential use. Use of novel renal epithelial markers hKIM-1 (clone AKG7) and/or PAX-8 and the adrenocortical marker SF-1 in an immunohistochemical panel for distinguishing adrenal cortical lesions from metastatic CC-RCC offers improved diagnostic sensitivity and specificity.

Immunohistochemical Diagnosis of Renal Neoplasms

Histologic diagnosis of renal neoplasm is usually straightforward by routine light microscopy. However, immunomarkers may be essential in several contexts, including differentiating renal from nonrenal neoplasms, subtyping of renal cell carcinoma (RCC), and diagnosing rare types of renal neoplasms or metastatic RCC in small biopsy specimens. To provide a comprehensive review of the diagnostic utility of immunomarkers for renal neoplasms. This review is based on published literature and personal experience. The following markers may have diagnostic utility in various diagnostic contexts: cytokeratins, vimentin, α-methylacyl coenzyme A racemase, carbonic anhydrase IX, PAX2, PAX8, RCC marker, CD10, E-cadherin, kidney-specific cadherin, parvalbumin, claudin-7, claudin-8, S100A1, CD82, CD117, TFE3, thrombomodulin, uroplakin III, p63, and S100P. Cytokeratins are uniformly expressed by RCC, albeit in a somewhat limited amount in some subtypes, requiring broad-spectrum anti-CK antibodies, including both low- and high-molecular-weight cytokeratins. PAX2 and PAX8 are sensitive and relatively specific markers for renal neoplasm, regardless of subtype. CD10 and RCC marker are sensitive to renal cell neoplasms derived from proximal tubules, including clear cell and papillary RCCs. Kidney-specific cadherin, parvalbumin, claudin-7, and claudin-8 are sensitive markers for renal neoplasms from distal portions of the nephron, including chromophobe RCC and oncocytoma. CK7 and α-methylacyl coenzyme A racemase are sensitive markers for papillary RCC; TFE3 expression is essential in confirming the diagnosis of Xp11 translocation RCC. The potentially difficult differential diagnosis between chromophobe RCC and oncocytoma may be facilitated by S100A1 and CD82. Thrombomodulin, uroplakin III, p63, and S100P are useful markers for urothelial carcinoma. Together with high-molecular-weight cytokeratins, PAX2, and PAX8, they can help differentiate renal pelvic urothelial carcinoma from collecting duct RCC. A sensitive marker for sarcomatoid RCC is still not available. Immunomarkers are most often used for diagnosing metastatic RCC. Compared with primary RCC, expression of the above-mentioned markers is often less frequent and less diffuse in the metastatic setting. Recognizing the variable sensitivity and specificity of these markers, it is important to include at least CD10, RCC marker, PAX2, and PAX8 in the diagnostic panel.

Immunohistochemical diagnosis of renal neoplasms.

Abstract Context—Histologic diagnosis of renal neoplasm is usually straightforward by routine light microscopy. However, immunomarkers may be essential in several contexts, including differentiating renal from nonrenal neoplasms, subtyping of renal cell carcinoma (RCC), and diagnosing rare types of renal neoplasms or metastatic RCC in small biopsy specimens. Objective—To provide a comprehensive review of the diagnostic utility of immunomarkers for renal neoplasms. Design—This review is based on published literature and personal experience. Conclusions—The following markers may have diagnostic utility in various diagnostic contexts: cytokeratins, vimentin, α-methylacyl coenzyme A racemase, carbonic anhydrase IX, PAX2, PAX8, RCC marker, CD10, E-cadherin, kidney-specific cadherin, parvalbumin, claudin-7, claudin-8, S100A1, CD82, CD117, TFE3, thrombomodulin, uroplakin III, p63, and S100P. Cytokeratins are uniformly expressed by RCC, albeit in a somewhat limited amount in some subtypes, requiring broad-spectru...

Birt-Hogg-Dubé syndrome: clinical and genetic studies of 10 French families

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant genodermatosis predisposing to the development of multiple fibrofolliculomas (FFs), pulmonary cysts, spontaneous pneumothorax and renal neoplasms. The association of BHDS with various nonrenal neoplasms has been reported but remains controversial. To report the clinical features and germline mutations in 22 patients from 10 unrelated families with BHDS investigated during a 5-year prospective study by the Department of Dermatology at the University Hospital of Montpellier, France. Also, to define more clearly the characteristics of pulmonary, thyroid, renal and colorectal manifestations associated with BHDS. Twenty-two patients with clinical and histological criteria of BHDS confirmed by FLCN (previously BHD) germline mutation were evaluated. Lung cysts and pneumothorax were detected by thoracic computed tomography (CT) scanning. Abdominal magnetic resonance imaging (MRI) or CT scans and/or renal ultrasonography were performed to screen for tumours. Thyroid nodules and goitres were assessed by clinical examination, ultrasound imaging and measurement of serum thyroid-stimulating hormone and thyrocalcitonin. Eighteen of the 22 individuals affected by BHDS (82%) were diagnosed with five or more FFs. Multiple epidermal cysts, severe facial hyperseborrhoea and oral papules were noted, respectively, in three of 22 (14%), nine of 22 (41%) and nine of 21 patients (43%). Spontaneous pneumothorax was reported in seven affected patients (32%). Cystic lesions were detected in 14 of 20 patients (70%) and mainly displayed a subpleural and basal location. Renal ultrasound, CT scan and/or MRI revealed renal cysts in 10 patients (45%), without renal carcinoma diagnosed thus far. Thyroid nodules and/or cysts were disclosed by ultrasound examination in 13 of 20 cases (65%). No medullary carcinoma or other thyroid carcinomas were detected. Colonoscopy failed to detect colorectal carcinoma. We report here the largest series to date of French patients with BHDS. We noted a high prevalence of thyroid nodules and renal cysts. However, the lack of a control group does not allow assessment of whether or not such association with BHDS is fortuitous.

The Utility of PAX-2 in Distinguishing Metastatic Clear Cell Renal Cell Carcinoma From its Morphologic Mimics

PAX-2 is a homeogene expressed during kidney development. Although immunohistochemical expression of PAX-2 has been described in a variety of primary renal cell carcinoma (RCC) subtypes and in metastatic RCC, its specificity as a marker of renal lineage in a metastatic setting has not been fully evaluated. In addition, its utility has not been directly compared with the most widely used antibody in this setting, renal cell carcinoma marker (RCCma). We studied PAX-2 expression in metastatic clear cell renal cell carcinoma (CC-RCC) and in a variety of nonrenal neoplasms with clear cytoplasm that may potentially mimic CC-RCC. Archival material from 27 CC-RCCs metastatic to various organs and 50 close morphologic mimics of CC-RCC were retrieved. Immunohistochemistry with PAX-2 and RCCmapi antibodies was performed on each case. Nuclear staining (PAX-2) or membranous staining (RCCma) was scored semiquantitatively. Twenty-three of 27 (85%) metastatic CC-RCCs showed nuclear immunoreactivity for PAX-2, whereas RCCma reactivity was found in 19 of 27 (70%). The immunoprofiles of the metastatic CC-RCC were PAX-2+/RCCma+: 19 of 27 (70%), PAX-2+/RCCma-: 5 of 27 (19%), PAX-2-/RCCma+: 2 of 27 (7%), and PAX-2-/RCCma-: 1 of 27 (4%). Five of the 50 mimics of CC-RCC (10%) had at least focal nuclear reactivity with PAX-2, including 1 of 3 parathyroid carcinomas (33%), 3 of 7 clear cell carcinomas of the ovary (43%), and the 1 clear cell papillary cystadenoma of the epididymis. Membranous RCCma reactivity was identified in 26 of the 50 mimics (52%). We conclude that PAX-2 is a useful marker for distinguishing metastatic CC-RCC from its potential morphologic mimics, but caution must be used in certain differential diagnostic settings where nonrenal tumors such as parathyroid carcinoma, ovarian clear cell carcinoma, and clear cell papillary cystadenoma of the epididymis were shown to express both PAX-2 and RCCma.

Immunohistochemical Detection of the von Hippel-Lindau Gene Product (pVHL) in Human Tissues and Tumors

Genetic alteration of the von Hippel-Lindau (VHL) tumor suppressor gene has been linked to hereditary and sporadic clear cell renal cell carcinomas (RCCs). Inconsistent data on immunodetection of the VHL gene product (pVHL) in normal tissues and tumors have been reported. We immunohistochemically reevaluated the usefulness of a specific rabbit polyclonal anti-pVHL antibody in 531 cases of renal and nonrenal neoplasms and normal tissues. Positive immunostaining was observed in nearly 100% of primary renal neoplasms, 95% of metastatic RCCs, and 90% of clear cell carcinomas of the ovary and uterus. In normal tissues, positive immunoreactivity was observed only in renal tubules, exocrine pancreas, islets, and bile ducts. Western blot and reverse transcription-polymerase chain reaction confirmed the immunostaining results. These data indicate that this anti-pVHL antibody is a useful marker in assisting diagnosis of metastatic RCC and may serve as a diagnostic marker for clear cell carcinomas of the ovary and uterus.

Immunohistochemical detection of P504S in primary and metastatic renal cell carcinomas.

P504S/alpha-methylacryl CoA racemase has been shown to be a relatively sensitive and specific positive marker for prostatic adenocarcinoma. The potential utility of P504S in renal cell neoplasms has not been explored in a large series. We assessed the diagnostic value of P504S in 332 cases of nonprostatic neoplasms using the avidin-biotin-peroxidase complex technique, including 115 renal neoplasms, 28 metastatic renal cell carcinomas (RCCs), and 189 nonrenal neoplasms. The results demonstrated that a granular, cytoplasmic staining pattern for P504S was observed in 48 of 70 (68.6%) conventional (clear cell) RCCs, 15 of 15 (100%) papillary RCCs, 2 of 7 (29%) chromophobe RCCs, and 2 of 8 (25%) oncocytomas. Among the 70 cases of clear cell RCC, positivity of P504S was seen in 40%, 71%, 94%, and 75% of RCCs with Furhman nuclear grade I, II, III, and IV, respectively. Strong immunostaining was present in each case (86/86) in the proximal tubules adjacent to the renal neoplasm. Eighty-two percent of metastatic RCCs (23/28) were positive for P504S. However, only 24 of 189 (13%) nonrenal malignancies were positive. The 24 positive cases included 12 of 13 (92%) colorectal adenocarcinomas, 6 of 30 (20%) ductal carcinomas of the breast, and 4 of 23 (17%) adenocarcinomas of the lung. These findings suggest that P504S is a useful marker in diagnosing primary and metastatic RCCs, although it has little value in differentiating chromophobe RCC from oncocytoma.

Non-renal Neoplasms and the Kidney

Non-renal Neoplasms and the Kidney