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      Lung tumor in a young African American patient with sickle trait: Pieces of a puzzle

      , MD, , MD, , MD, , MD, , MD, , MD *


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          PERTINENT CLINICAL HISTORY TO GUIDE THE QUIZ A 32-year-old African American male with sickle cell trait presented with headaches, nausea, vomiting, cough, pleuritic chest pain, hypertension, and a 10-pound weight loss. A computed tomography (CT) showed multiple lung nodules, mediastinal lymphadenopathy, and an 11 cm mass in the right kidney with a suspicion for a tumor thrombus in the renal vein. Figure 1a–d shows an abdominal CT, cytomorphological features, and an hematoxylin and eosin (H and E) of the lung core biopsy. Figure 1 (a) Computed tomography scan of the abdomen showing an 11 cm right renal mass. (b and c) Touch imprints of the lung core biopsy showing malignant cells arranged singly and in loose clusters with large, hyperchromatic nuclei, irregular nuclear contours and a moderate amount of granular cytoplasm with dense eosinophilic cytoplasmic globules (Diff-Quik stain, ×400). (d) Core biopsy showing malignant cells arranged in nests with areas of cribriform pattern and acute inflammation in a background of stromal fibrosis. Many cells demonstrate rhabdoid features. (H and E, ×400) WHAT IS YOUR INTERPRETATION? Metastatic clear cell renal cell carcinoma (RCC) Primary lung non small cell carcinoma Metastatic renal medullary carcinoma (RMC) Metastatic high-grade urothelial carcinoma. ANSWER The correct cytopathologic interpretation is: c. Metastatic renal medullary carcinoma (RMC) BRIEF DISCUSSION WITH FOLLOW-UP RMC is a high-grade malignancy with a poor prognosis. It affects predominantly young patients of African descent (median age 22 years, range 5–69 years). Ninety-six percent of the patients are younger than 40 years of age with a male to female ratio of 2.4:1. Eighty-eight percent of the patients have sickle cell trait.[1] It has a poor prognosis with an overall survival of 4 months in patients with metastases and 17 months without.[2] Widely metastatic disease at the time of diagnosis is typical. The rarity of this cancer poses a significant challenge in diagnosis and management. Rare publications have described cytologic features of RMC.[3 4 5 6 7 8 9] Cytologically, the tumor cells have been described to be present in sheets, loosely cohesive clusters, or singly. They have high-grade nuclear features with hyperchromatic, enlarged, pleomorphic nuclei, and prominent nucleoli in most cases. The cytoplasm is moderate to abundant and contains vacuoles, cytoplasmic lumina, and eosinophilic globules. Different patterns have been described on histologic sections, with a cribriform architecture being the most common. Other growth patterns including microcystic, tubular, trabecular, solid, sarcomatoid, and yolk sac-like have also been described. Stromal desmoplasia along with prominent acute and chronic inflammation is present in most cases. The cells typically have abundant eosinophilic cytoplasm, with eosinophilic cytoplasmic inclusions resembling rhabdoid tumors in some cases. RMC is positive for cytokeratin AE1/AE3, low molecular weight cytokeratin, vimentin, and PAX8. It is negative for high molecular weight cytokeratin (HMWCK). Staining for CK7 and CK20 is variable ranging from no staining to diffuse staining.[10] RMC shows loss of INI-1 staining. INI-1 (hSNF5/SMARCB1/BAF47) is a highly conserved factor in ATP-dependent chromatin-modifying complex. Loss of INI-1 is associated with aggressive tumor behavior and has been reported in tumors such as pediatric renal and extrarenal malignant rhabdoid tumors, atypical teratoid/rhabdoid tumors of the central nervous system, epithelioid sarcomas, approximately 50% of epithelioid malignant peripheral nerve sheath tumors (MPNSTs), some myoepithelial carcinomas and extraskeletal myxoid chondrosarcomas (EMCSs).[11] Ultrastructurally, the tumor cells have no consistent abnormalities. In some cases, tumor cells display tight junctions and intracellular lumen with microvilli.[12 13] H and E and immunohistochemistry (IHC) results of the core biopsy in our case are presented in Figure 2a–f. In addition, TTF-1 and Napsin-A IHC performed on the core biopsy were negative. Figure 2 (a) Nests of malignant cells in a background of desmoplastic stroma and acute and chronic inflammation (H and E, ×200). (b) CK7 demonstrates diffuse cytoplasmic staining (×400). (c) CK20 demonstrates strong cytoplasmic staining (×400). (d) Vimentin demonstrates patchy positive staining in malignant cells (×400). (e) PAX8 demonstrates diffuse nuclear staining (×400). (f) INI-1 demonstrates loss of nuclear staining (×400) ADDITIONAL QUIZ QUESTIONS Q1. Which of the following statements is FALSE about renal medullary carcinoma? It affects predominantly young patients of African descent It is an aggressive tumor with a poor prognosis It arises predominantly in the right kidney High partial oxygen pressure and alkaline pH of the renal medulla in patients with sickle cell trait contribute to the mutagenesis and tumor formation. Q2. RMC is thought to arise from the: Proximal renal tubules Distal renal tubules Distal/terminal collecting ducts Urothelium. Q3. Which of the following IHC panels is characteristic of RMC? HMWCK−, INI-1−, Vimentin+, PAX8+ HMWCK+, INI-1−, Vimentin+, PAX8− HMWCK−, INI-1+, Vimentin+, PAX8+ HMWCK+, INI-1+, Vimentin−, PAX8+ Q4. What other tumors typically demonstrate INI-1 staining pattern that is similar to RMC? Extrarenal malignant rhabdoid tumor Atypical teratoid/rhabdoid tumor Epithelioid sarcoma All of the above. ANSWERS TO ADDITIONAL QUIZ QUESTIONS Q1 (d); Q2 (c); Q3 (a); Q4 (d) Q1 (d): RMC is an aggressive malignant tumor with a poor prognosis. It is seen predominantly in young patients of African descent with sickle cell trait. Greater than 75% of RMC originate in the right kidney.[12] The low partial oxygen pressure and acid pH of the renal medulla promote chronic hemoglobin sickling and contribute to chronic ischemia, hypoxia, and vaso-occlusion, which are thought to promote mutagenesis.[10] Q2 (c): RMC is thought to arise from the epithelium of the distal/terminal collecting ducts. Q3 (a): RMC is positive for cytokeratin AE1/AE3, low molecular weight cytokeratin, vimentin, and PAX8. It is negative for HMWCK and demonstrates loss of nuclear INI-1 (hSNF5/SMARCB1/BAF47) staining. Staining for CK7 and CK20 is variable ranging from no staining to diffuse staining. Q4 (d): INI-1 is a highly conserved factor in ATP-dependent chromatin remodeling complex. In addition to RMC, other tumors with absent INI-1 are pediatric renal and extrarenal malignant rhabdoid tumors, atypical teratoid/rhabdoid tumors of the central nervous system, and epithelioid sarcomas. Some epithelioid MPNST, a proportion of myoepithelial carcinoma, and EMCS also show loss of INI-1 staining.[11] BRIEF REVIEW OF THE TOPIC RMC arises in the renal medulla. It was first described in 1995 by Davis et al.,[14] who dubbed it as the “seventh sickle cell nephropathy;” the other six being hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate urine, and pyelonephritis. These latter six pathologic changes seen in the renal medulla are associated with the chronic sickling process. The acid pH and hyperosmolar microenvironment of the medulla contribute to the increase in intracellular concentration and polymerization of hemoglobin S. The partial oxygen pressure in the renal medulla is 35–40 mmHg, below the 45 mmHg threshold for sickling. All these factors are thought to promote sickling not only in individuals with sickle cell disease but also in those with sickle cell trait. The pathologic sequelae of chronic sickling include chronic ischemia, hypoxia, and vaso-occlusion, all of which may promote mutagenesis and neoplastic transformation in the damaged renal medulla.[10] RMC is thought to arise from the epithelium of the distal/terminal collecting ducts and has been proposed as a variant of CDC of the kidney. It has been hypothesized that chronic sickling increases levels of hypoxia-inducible factor (HIF), a transcription factor that regulates the expression of various genes. It induces TP53, which regulates cell death through apoptosis. In tumors lacking TP53, HIF induces vascular endothelial growth factor, promoting neovascularization, thus causing cancer progression.[10] Yang et al. studied molecular profiling of RMC using comparative genomic hybridization comparing the expression pattern of different genes in renal medullary carcinoma with all other types of renal tumors. They discovered that renal medullary carcinoma clustered most closely with urothelial carcinoma. Both have markedly elevated extracellular matrix genes, such as laminin alpha 3 and gamma 2, fibronectin 1, collagen Type III, and fibulin 2. Several genes are overexpressed in RMC, such as topoisomerase II, macrophage-stimulating 1 receptor, and angiogenesis-related genes, including peroxisome proliferator-activated receptor gamma angiopoietin -related gene.[15] The common presenting complaints are hematuria and flank pain; whereas respiratory issues from bulky disease or pleural effusion are typically seen in <10% of presentations.[2] Interestingly, despite the left kidney being the most common location of benign hematuria, >75% of RMC originate in the right kidney.[12] Metastases at presentation are frequent. The most common metastatic sites include lymph nodes, lungs, liver, adrenal glands, and bone.[1] Some patients first present with signs of metastatic disease as was seen in our patient who presented with cough and shortness of breath. RMC shows a variable architectural pattern including cribriform, reticular, yolk sac, adenoid cystic-like, trabecular, infiltrating solid cords, or papillae with central fibrovascular cores. Stroma is hypocellular, myxoid, edematous, with desmoplastic reaction and inflammatory infiltrate.[16 17 18] Cytologically, the tumor cells are arranged in loosely cohesive clusters or dispersed singly. They have pleomorphic nuclei, prominent nucleoli, irregular nuclear membranes, distinct cell borders, and cytoplasmic vacuoles and often demonstrate rhabdoid features. Inflammation, stromal fragments, and sickle red blood cells may be present in the background.[3 4 5 6 7 8 9 19] The tumor cells are positive for mucin, typically positive for CK7, and vimentin (focal) and are negative for HMWCK, with only a few cases reported as positive for ulex europaeus agglutinin 1 lectin (UEA-1). Morphologically, RMC can be confused with CDC as both tumors arise in the renal medulla. In fact, some publications described RMC as a subtype of CDC. Clinical presentation, morphology, and immunostains help differentiate these two tumor types. CDC occurs in older patients and is not associated with sickle cell trait/disease. It demonstrates tubular, tubulopapillary, and glandular structures and solid and/or nested growth patterns. Intraluminal basophilic to amphophilic mucin may be present. Stroma is myxoid to sclerotic with desmoplastic stromal reaction with or without inflammation.[16] Cytologic preparations are variably cellular and demonstrate medium-sized tumor cells with high nucleocytoplasmic ratios, large pleomorphic nuclei, coarse chromatin, inconspicuous to prominent nucleoli, and scant to moderate finely granular cytoplasm. Occasionally, intracytoplasmic mucin may be present.[19] The tumor cells are positive for HMWCK, UEA-1,[10 20] and generally CK7, but not CK20. High-grade urothelial carcinoma and RMC have some morphologic similarities, most notably the infiltrating growth pattern. The cells have relatively dense cytoplasm and nuclei with obvious malignant features, including pleomorphism, course chromatin, and prominent nucleoli.[19] Urothelial carcinoma is positive for HMWCK and p63, and many tumors are positive for both CK7 and CK20. RMC shows variable staining with CK7 and CK20 and is HMWCK and p63 negative. The differential diagnosis of RMC also includes high-grade conventional clear cell RCC, which can grow in a variety of patterns including solid, alveolar, and acinar with numerous thin-walled blood vessels. Cytologically, high-grade RCC is arranged in clusters or sheets, sometimes with floral groups or short papillae that occasionally contain metachromatic basement membrane-like material. The cells have delicate wispy or finely vacuolated cytoplasm and centrally or eccentrically located large, pleomorphic nuclei with prominent nucleoli.[19] Like RMC, high-grade RCC may show rhabdoid features; however, it is typically negative for both CK7 and CK20. In addition, the majority of RMC show loss of nuclear staining for INI-1 whereas the staining is retained in RCC, UC, and CDC, even those with rhabdoid morphology. Treatment for RMC is challenging due to the rarity of this tumor with a mean survival of less than a year. Neither chemotherapy nor radiation therapy is particularly effective. The current therapeutic approach with these aggressive tumors is radical nephrectomy followed by cytotoxic chemotherapy, but the prognosis remains dismal. A few newer treatment approaches including both cytotoxic chemotherapy and targeted therapy regimens have been shown to slightly increase average survival in small cohorts.[20 21] SUMMARY Reported cases of RMC describing cytologic features and immunohistochemical characteristics are few and without long-term follow-up. A high index of suspicion in patients with known risk factors might prove to be helpful in early detection. Further studies with larger patient cohorts are needed to understand this rare malignancy. COMPETING INTERESTS STATEMENT BY ALL AUTHORS All authors declare that they have no competing interests. AUTHORSHIP STATEMENT BY ALL AUTHORS MM collected the details of the case, carried out literature review and drafted and edited the manuscript. MP collected the details of the case, performed photomicrographs, additional literature review and edited the manuscript. KM was involved in conceptualization and edited the manuscript. JT helped edit the manuscript. SH helped edit the manuscript. EL conceptualized the quiz case, performed additional literature review, and edited the manuscript. All authors read and approved the final manuscript. ETHICS STATEMENT BY ALL AUTHORS This report does not require approval from Institutional Review Board. LIST OF ABBREVIATIONS (In alphabetic order) CT − Computed tomography EMCS − Extraskeletal myxoid chondrosarcoma H and E − hematoxylin and eosin HIF – Hypoxia inducible factor HMWCK − High molecular weight cytokeratin IHC – Immunohistochemistry MPNST − Malignant peripheral nerve sheath tumor RCC − Renal cell carcinoma RMC – Renal medullary carcinoma UEA 1 − Ulex europaeus agglutinin 1 lectin. EDITORIAL/PEER-REVIEW STATEMENT To ensure the integrity and highest quality of CytoJournal publications, the review process of this manuscript was conducted under a double-blind model (authors are blinded for reviewers and vice versa) through automatic online system.

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          Most cited references 21

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          INI1-deficient tumors: diagnostic features and molecular genetics.

          Significant progress has been made in understanding the molecular genetic alterations involved in sarcomagenesis. Cytogenetic and molecular studies have identified nonrandom genetic abnormalities, including tumor suppressor gene inactivation. Mutations, deletions, and other somatic alterations in the tumor suppressor gene INI1 (hSNF5; SMARCB1), which encodes a subunit of the SWI/SNF chromatin remodeling complex, were first described in the malignant rhabdoid tumor of infancy. Since then, INI1 has also been implicated in the pathogenesis of additional tumor types including renal medullary carcinomas and epithelioid sarcomas and a subset of epithelioid malignant peripheral nerve sheath tumors, myoepithelial carcinomas, and extraskeletal myxoid chondrosarcomas. As varied as this group appears, they all show loss of INI1 protein expression, a propensity for rhabdoid cytomorphology, and sometimes other overlapping immunohistochemical and histologic findings. We will review the clinicopathologic features of these tumor types and emphasize the clinical utility of INI1 immunohistochemistry in differential diagnosis.
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            Renal medullary carcinoma. The seventh sickle cell nephropathy.

            Over the last 22 years, we have encountered 34 examples of a highly aggressive neoplasm with a microscopic morphology that is highly predictive of finding sickled erythrocytes in the tissue. With the exception of one patient, all are believed to have had sickle cell trait or, in one case, hemoglobin SC disease. These 33 patients are the subject of this report and, where their race was known, they were all blacks between the ages of 11 and 39 years. Between the ages of 11 and 24 years, males predominated by 3 to 1. Beyond age 24, however, the tumors occurred equally in men and women. The dominant tumor mass was in the medulla and ranged from 4 to 12 cm in diameter. Mean size was 7 cm; median, 6 cm. Peripheral satellites in the renal cortex and pelvic soft tissues, as well as venous and lymphatic invasion, were usually present. The lesions exhibited a reticular, yolk sac-like, or adenoid cystic appearance, often with poorly differentiated areas in a highly desmoplastic stroma admixed with neutrophils and usually marginated by lymphocytes. The tumors had usually metastasized when first discovered, and none was confined to the kidney at the time of nephrectomy. The mean duration of life after surgery was 15 weeks. These tumors probably arise in the calyceal epithelium in or near the renal papillae, the same site that produces the more familiar picture of unilateral hematuria in patients with sickle cell trait. We have concluded that renal medullary carcinoma represents another example of renal disease associated with sickle cell disorders. The other six are unilateral hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate urine, and pyelonephritis.
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              Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications.

              To investigate the pathologic, clinical, and genetic features of renal medullary carcinomas (RMCs) in search of clues to their pathogenesis. We analyzed 40 RMCs for clinical features, for immunohistochemical expression using a panel of markers, and for genetic changes using comparative genomic hybridization. Patients presented at 5 to 32 years of age, and 82% were African American. All patients tested had sickle cell trait or disease. Seven patients presented with suspected renal abscess or urinary track infection without a clinically recognizable mass. Of the 15 tumors able to be analyzed, all were positive for epithelial markers CAM 5.2 and epithelial membrane antigen. All were negative for high-molecular-weight cytokeratin 34betaE12. Cytokeratins 7 and 20 and carcinoembryonic antigen were heterogeneous and variable. Ulex was focally positive in a minority of cases. Eight of 12 tumors showed significant positivity for TP53 protein (greater than 25% nuclear positivity). All tumor tested (n = 8) were strongly positive for vascular endothelial growth factor and hypoxia inducible factor. Of nine tumors analyzed for genetic gains and losses using comparative genomic hybridization, eight showed no changes and one showed loss of chromosome 22. Survival ranged from 2 weeks to 15 months (mean 4 months). These findings suggest that RMC is clinically and pathologically distinct from collecting duct carcinoma. The hypothesis that chronic medullary hypoxia secondary to hemoglobinopathy may be involved in the pathogenesis of RMC is suggested by strong vascular endothelial growth factor and hypoxia inducible factor expression and positivity for TP53.

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                Medknow Publications & Media Pvt Ltd (India )
                27 August 2018
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                Address: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
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                Copyright: © 2018 Mir, et al.; Licensee Cytopathology Foundation Inc.

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