VCL-ALK renal cell carcinoma in adult patient without sickle cell trait

Anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC) is a provisional renal cell carcinoma subtype with a growing list of published fusion partners. VCL-ALK gene fusion represents an uncommon fusion partner (only 6 reported cases), almost always associated with sickle cell trait and typically in a pediatric population. Herein, we report only the second case of VCL-ALK gene fusion ALK-RCC from a 31-year-old female without associated sickle cell trait, and also only the third reported case occurring in an adult patient. The tumor (measuring 8.5 cm and confined to the kidney) demonstrated mostly solid growth, pleomorphic nuclei, variably rhabdoid to vacuolated cytoplasm, and showed diffuse strong immunoreactivity for both PAX8 and ALK stains. Gene panel sequencing confirmed VCL-ALK gene fusion in the tumor. This study expands the clinical framework for diagnostic consideration of this rare tumor with potential targeted pharmacotherapy

Systematic analysis of breast cancer morphology uncovers stromal features associated with survival

The morphological interpretation of histologic sections forms the basis of diagnosis and prognostication for cancer. In the diagnosis of carcinomas, pathologists perform a semiquantitative analysis of a small set of morphological features to determine the cancer's histologic grade. Physicians use histologic grade to inform their assessment of a carcinoma's aggressiveness and a patient's prognosis. Nevertheless, the determination of grade in breast cancer examines only a small set of morphological features of breast cancer epithelial cells, which has been largely unchanged since the 1920s. A comprehensive analysis of automatically quantitated morphological features could identify characteristics of prognostic relevance and provide an accurate and reproducible means for assessing prognosis from microscopic image data. We developed the C-Path (Computational Pathologist) system to measure a rich quantitative feature set from the breast cancer epithelium and stroma (6642 features), including both standard morphometric descriptors of image objects and higher-level contextual, relational, and global image features. These measurements were used to construct a prognostic model. We applied the C-Path system to microscopic images from two independent cohorts of breast cancer patients [from the Netherlands Cancer Institute (NKI) cohort, n = 248, and the Vancouver General Hospital (VGH) cohort, n = 328]. The prognostic model score generated by our system was strongly associated with overall survival in both the NKI and the VGH cohorts (both log-rank P ≤ 0.001). This association was independent of clinical, pathological, and molecular factors. Three stromal features were significantly associated with survival, and this association was stronger than the association of survival with epithelial characteristics in the model. These findings implicate stromal morphologic structure as a previously unrecognized prognostic determinant for breast cance

Renal leiomyoma: A contemporary multi-institution study of an infrequent and frequently misclassified neoplasm

Renal leiomyoma is an exceptionally rare benign mesenchymal tumor of the kidney predominantly arising in proximity of the renal capsule or pelvis. Its rarity and nonspecific clinical and imaging features may lead to radical or partial nephrectomy on the basis of preoperative suspicion of renal cell carcinoma. The diagnosis of renal leiomyoma is challenging because of the histologic overlap with lipid-poor angiomyolipoma (AML). We conducted a multi-institution study to characterize renal leiomyoma in greater detail. We collected and reviewed 24 cases diagnosed initially as renal leiomyoma in 10 institutions from North America, Canada, and Europe. Immunohistochemical expression of desmin, HMB-45, estrogen receptor (ER), progesterone receptor (PR), and cathepsin K was evaluated. Upon central review, 9 tumors were classified as renal leiomyoma, whereas the remaining were reclassified as AML (n=13), myolipoma (n=1), and medullary fibroma (n=1). All renal leiomyomas were solitary and occurred in female patients (mean age 63 y; range, 44 to 74 y). Tumor size ranged from 0.6 to 7.0 cm (mean 2.9 cm); 7 originated from the renal capsule or the subcapsular area and 1 from a large vessel in the renal sinus. All leiomyomas were diffusely positive for desmin and negative for HMB-45 and cathepsin K; 6/9 (67%) showed diffuse ER and PR expression, and 1 case showed focal ER positivity only. Renal leiomyoma should be included in the histologic differential diagnosis of solid renal masses, particularly in perimenopausal women. The main differential diagnosis is with lipid-poor AML, and cathepsin K plays a key role in distinguishing these 2 lesions

Tuberous sclerosis complex: Hamartin and tuberin expression in renal cysts and its discordant expression in renal neoplasms

Tuberous sclerosis complex (TSC) results from mutation of TSC1 or TSC2 that encode for hamartin and tuberin. It affects the kidneys often in advance of extra-renal stigmata. We studied 14 TSC cases, and 4 possible TSC cases with multiple angiomyolipomas (AMLs) for hamartin and tuberin protein expression to determine if the staining profile could predict mutation status or likelihood of TSC with renal-limited disease. The 18 cases included 15 nephrectomies and 1 section of 6 TSC-associated renal cell carcinomas (RCC). Controls included the non-neoplastic kidney in 5 tumor nephrectomies, 4 sporadic cases of AML and 6 clear cell RCCs. In the 14 TSC cases, 9 had AMLs, 9 had RCCs, 5 had polycystic kidney disease and 8 had eosinophilic cysts (EC) lined by large eosinophilic cells. The controls and study cases showed luminal staining of proximal tubules (PT) and peripheral membrane staining in distal tubules/collecting ducts for hamartin and cytoplasmic staining for tuberin. Eosinophilic cysts had a luminal PT-like stain with hamartin and a cytoplasmic reaction for tuberin. Hamartin stained myoid cells in all AMLs. Tuberin was negative in all but 1AML, an epithelioid AML. All but 1 RCC were positive for tuberin; 13 RCCs (7 TSC/6 non-TSC) were negative for hamartin and 4 showed a weak reaction. We conclude that the ECs of TSC are proximal tubule-derived. The hamartin and tuberin staining profiles of AMLs and most RCCs are reciprocal precluding prediction of the mutation in TSC, and fail to predict if a patient with multifocal AML has TSC

Low-grade Oncocytic Tumor of Kidney (CD117 Negative, Cytokeratin 7 Positive): A Distinct Entity?

Aim To describe a group of distinct low‐grade oncocytic renal tumors that demonstrate CD117 negative/Cytokeratin (CK) 7 positive immunoprofile. Methods and results We identified 28 such tumors from 4 large renal tumor archives. We performed immunohistochemistry for: CK7, CD117, PAX8, CD10, AMACR, e‐cadherin, CK20, CA9, AE1/AE3, vimentin, BerEP4, MOC31, CK5/6, p63, HMB45, melan A, CD15 and FH. In 14 cases we performed array CGH; in 9 cases with successful result. Median patient age was 66 years (range 49‐78 years) with a male‐to‐female ratio of 1:1.8. Median tumor size was 3 cm (range 1.1‐13.5 cm). All were single tumors, solid and tan‐brown, without a syndromic association. On microscopy, all cases showed solid and compact nested growth. There were frequent areas of edematous stroma with loosely arranged cells. The tumor cells had oncocytic cytoplasm with uniformly round to oval nuclei, but without significant irregularities, and showed only focal perinuclear halos. Negative CD117 and positive CK7 reactivity were present in all cases (in 2 cases there was focal and very weak CD117 reactivity). Uniform reactivity was found for: PAX8, AE1/AE3, e‐cadherin, BerEP4 and MOC31. Negative stains included: CA9, CK20, vimentin, CK5/6, p63, HMB45, Melan A and CD15. CD10 and AMACR were either negative or focally positive; FH was retained. On array CGH, there were frequent deletions at 19p13.3 (7/9), 1p36.33 (5/9) and 19q13.11 (4/9); disomic status was found in 2/9 cases. On follow‐up (mean 31.8 months, range 1‐118), all patients were alive with no disease progression. Conclusion Low‐grade oncocytic tumors that are CD117 negative/CK7positive demonstrate consistent and readily recognizable morphology, immunoprofile, and indolent behavior