Asli Yilmaz

Endometrial stromal sarcomas with unusual histologic features: A report of 24 primary and metastatic tumors emphasizing fibroblastic and smooth muscle differentiation

We report the clinicopathologic features of 24 uterine primary and metastatic endometrial stromal sarcomas with fibromyxoid features (ESS-F) and smooth muscle differentiation (ESS-SM) (endometrial stromal sarcoma variants). Two groups of tumors were retrieved from the surgical pathology files at Memorial Sloan-Kettering Cancer Center: 1) gynecologic mesenchymal neoplasms with striking smooth muscle or fibroblastic differentiation that did not meet the clinical or histologic criteria for leiomyosarcoma or other established neoplasms containing smooth muscle; and 2) metastatic lesions showing ovoid and spindle cell morphology, involving lung, originally diagnosed as low-grade leiomyosarcoma, low-grade smooth muscle neoplasm, intravenous leiomyomatosis, fibrous hamartoma, and benign metastasizing leiomyoma. We identified 12 patients with 30 tumors; 24 were available for review. The mean age was 51 years (range 21–74 years). Follow-up >1 year was available for eight patients, with a mean time of 8.5 years. Each patient had a uterine primary and 10 experienced metastases. Mean time to recurrence was 6.8 years. Sites of metastasis included lung, retroperitoneum, right atrium/inferior vena cava, colon, and ovaries. No patient died of disease, but in many cases the follow-up period ended with the discovery of a metastasis. Four patients were originally diagnosed with endometrial stromal sarcoma, but other presenting diagnoses included benign metastasizing leiomyoma, fibroleiomyomatous tumor of lung, smooth muscle tumor of uncertain or low malignant potential, and intravascular leiomyomatosis. On review each patient had at least one tumor (primary and/or metastasis) that was determined to be an endometrial stromal sarcoma variant. Review diagnoses were as follows: endometrial stromal sarcoma (nonvariant), ESS-F, and ESS-SM. Eight of 10 primary tumors with available slides were endometrial stomal sarcoma variants (six ESS-F and two ESS-SM). When these variant features were present, they comprised between 50% and 100% of the neoplasm. The variant histology tumors exhibited prominent spiral arterioles, perivascular edema, and stromal cell condensation around blood vessels. All metastases but one were variant tumors; eight were ESS-F and five were ESS-SM. Four metastases did not resemble the uterine primary. Desmin marked smooth muscle mostly but not specifically. h-Caldesmon marked smooth muscle exclusively. Endometrial stromal cells as well as some fibroblasts and smooth muscle cells expressed CD10. We conclude that the presence of even focal endometrial stromal differentiation in an invasive uterine mesenchymal lesion with a predominant low-grade smooth muscle, fibroblastic, and/or myxoid phenotype should permit classification as low-grade sarcoma—they should be considered endometrial stromal sarcomas.

Succinate Dehydrogenase (SDH)-deficient Renal Carcinoma: A Morphologically Distinct Entity: A Clinicopathologic Series of 36 Tumors From 27 Patients

Succinate dehydrogenase (SDH)-deficient renal carcinoma has been accepted as a provisional entity in the 2013 International Society of Urological Pathology Vancouver Classification. To further define its morphologic and clinical features, we studied a multi-institutional cohort of 36 SDH-deficient renal carcinomas from 27 patients, including 21 previously unreported cases. We estimate that 0.05% to 0.2% of all renal carcinomas are SDH deficient. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M:F=1.7:1). Bilateral tumors were observed in 26% of patients. Thirty-four (94%) tumors demonstrated the previously reported morphology at least focally, which included: solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, and round to oval low-grade nuclei. All 17 patients who underwent genetic testing for mutation in the SDH subunits demonstrated germline mutations (16 in SDHB and 1 in SDHC). Nine of 27 (33%) patients developed metastatic disease, 2 of them after prolonged follow-up (5.5 and 30 y). Seven of 10 patients (70%) with high-grade nuclei metastasized as did all 4 patients with coagulative necrosis. Two of 17 (12%) patients with low-grade nuclei metastasized, and both had unbiopsied contralateral tumors, which may have been the origin of the metastatic disease. In conclusion, SDH-deficient renal carcinoma is a rare and unique type of renal carcinoma, exhibiting stereotypical morphologic features in the great majority of cases and showing a strong relationship with SDH germline mutation. Although this tumor may undergo dedifferentiation and metastasize, sometimes after a prolonged delay, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis.

A nomogram for predicting low-volume/low-grade prostate cancer: A tool in selecting patients for active surveillance

The authors reported previously that assessment of the number of positive biopsy cores, maximum tumor length in a core, Gleason score, and prostate volume in an extended biopsy enhanced the accuracy of predicting low‐volume/low‐grade prostate cancer. On the basis of those findings, they developed a nomogram to predict the probability of low‐volume/low‐grade prostate cancer specifically for men with a single positive biopsy core.

The impact of the 2005 International Society of Urological Pathology (ISUP) consensus on Gleason grading in contemporary practice

Aims:  To investigate the impact of the 2005 International Society of Urological Pathology (ISUP) Gleason grading consensus in contemporary practice.

Renal oncocytoma revisited: a clinicopathological study of 109 cases with emphasis on problematic diagnostic features

Trpkov K, Yilmaz A, Uzer D, Dishongh K M, Quick C M, Bismar T A & Gokden N
(2010) Histopathology57, 893–906

Glomus tumor of the kidney: a report of 3 cases involving renal parenchyma and review of the literature.

Glomus tumor is a rare mesenchymal neoplasm affecting the subcutaneous tissue of the distal extremities in the majority of cases. It only rarely involves visceral organs. We report 3 cases of the glomus tumor family in the kidney, a solid glomus tumor, a glomangioma, and a glomangiomyoma. All 3 tumors involved the renal parenchyma and occurred in 3 men aged 36, 81, and 48 years, respectively. All 3 tumors were well-circumscribed and showed morphology otherwise identical to those seen in soft tissue. All 3 tumors were immunoreactive for actin and negative for desmin and S100 and only 1 tumor expressed CD34 in tumor cells. To date, all 3 tumors have followed a benign course without evidence of recurrence or metastasis. This report expands the spectrum of mesenchymal tumors of the kidney.

Lipid-rich variant of pancreatic endocrine neoplasms

Most pancreatic endocrine neoplasms (PENs) show characteristic and well-recognized endocrine morphology; however, a lipid-rich pattern, which can present a diagnostic problem in biopsies, has been reported, mostly as individual cases. Some have been included in descriptions of the rare clear-cell variant associated with von Hippel-Lindau (VHL) syndrome. The histogenesis, clinicopathologic characteristics, and significance of this lipid-rich pattern have not been unraveled. In this study, 11 PENs exhibiting foamy, microvesicular cytoplasm were analyzed. In some cases, the nuclei were distorted by the vesicles, and the usual endocrine chromatin pattern was not evident. The growth pattern was relatively diffuse, with vague compartmentalization of the cells by a delicate vasculature; prominent nesting was noted in only 4 cases. Pathology reports indicated substantial diagnostic challenge in these cases; on biopsies, 1 case was originally diagnosed as adrenal cortical carcinoma, another as renal cell carcinoma, a third as solid-pseudopapillary tumor, and a fourth had a fine needle aspiration cytologic diagnosis of adenocarcinoma. All cases were chromogranin and synaptophysin positive. Electron microscopy in 3 cases confirmed the cytoplasmic vesicles to be lipid vacuoles. Neurosecretory granules were also evident. Clinically, as in conventional PENs, there appeared to be two distinct subsets: Two cases were familial or functional/syndromic (1 with VHL and the other with MEN-1 and glucagonoma syndrome) and occurred in younger adults (ages 41 and 47 years); the majority (n = 9) were nonfunctional/nonsyndromic and nonfamilial. The latter group was mostly represented by elderly males (mean age: 65 vs. 58 years in conventional sporadic PENs). Immunohistochemically, markers implicated in VHL-associated neoplasia, including HIF-1α, inhibin, and Melan-A (in clear-cell PENs) and MUC6 (in serous cystadenomas) were mostly negative in lipid-rich PENs (1 of 10, 1 of 10, 0 of 10 and 0 of 10, respectively). In conclusion, the lipid-rich pattern, reminiscent of adrenal cortical cells, represents a distinct subset of PENs. It presents a diagnostic challenge for surgical pathologists, especially in biopsies. EM supports the name lipid-rich for this variant. The findings suggest that the pathogenesis of lipid-rich tumors may be different from the VHL-associated clear-cell variants of PENs.

Prostate cancer with tertiary Gleason pattern 5 in prostate needle biopsy: clinicopathologic findings and disease progression.

Significance of tertiary Gleason pattern/grade 5 on prostatectomy has been studied, but its significance on biopsy remains uncertain. Recent International Society of Urological Pathology consensus conference recommended that biopsy Gleason score is generated by adding tertiary grade 5 to the primary grade. We examined the preoperative clinical and biopsy findings in 53 patients with biopsy tertiary pattern 5 and 119 patients with primary/secondary biopsy pattern 5. Prostatectomy findings and prostate-specific antigen (PSA) failure rates were compared in surgically treated patients. Cause-specific and all-cause mortality were compared in patients treated nonsurgically. At presentation, age, gland volume, PSA, and biopsy cancer volume were similar in patients with tertiary and primary/secondary grade 5. Only 20 patients underwent prostatectomy and 152 were treated nonsurgically. Regardless of the pattern, patients treated by prostatectomy were younger (P=0.003), had lower PSA (P=0.001), and less cancer on biopsy (P=0.0001). Prostatectomy findings and PSA failures were not significantly different in patients with tertiary grade 5 versus primary/secondary pattern 5. In nonsurgically treated patients, patients with primary pattern 5 compared with those with tertiary pattern 5 had a significantly higher risk of all-cause mortality [adjusted hazard ratio (HR): 2.33, 95% confidence interval (CI): 1.10-4.90, P=0.026] and cause-specific mortality (adjusted HR: 7.52, 95% CI: 2.84-19.87, P<0.001). In contrast, patients with secondary pattern 5 had a comparable all-cause mortality risk to patients with tertiary pattern 5 (adjusted HR: 1.04, 95% CI: 0.47-2.32, P=0.92), but had a marginally higher risk of cause-specific mortality than patients with tertiary pattern 5 (adjusted HR: 2.13, 95% CI: 0.75-6.10, P=0.16).

Usefulness of cytokeratin 5/6 and AMACR applied as double sequential immunostains for diagnostic assessment of problematic prostate specimens.

We evaluated the usefulness of double immunohistochemical staining for cytokeratin (CK)5/6 and alpha-methylacyl coenzyme A racemase (AMACR) applied sequentially on 1 slide by assessing 223 foci in 110 consecutive prostate specimens. Double-chromogen reaction was used to visualize the antibodies: brown for CK5/6 and red for AMACR. Staining was scored as diffuse, focal, or negative. To establish the diagnosis, CK5/6 and AMACR were correlated with the morphologic features. All cancers lacked CK5/6 staining (100% specificity). AMACR showed diffuse or focal positivity in cancer, high-grade prostatic intraepithelial neoplasia, and atypia in 96.8% (120/124), 85% (22/26), and 80% (16/20) of cases, respectively. In atypical cases, diagnosis was because of non-immunohistochemical staining reasons in 80% of cases. In adenosis (n = 14), AMACR was diffusely positive in 4 cases (29%). Double immunohistochemical staining for CK5/6 and AMACR is a simple assay to perform and may be used as an alternative to antibody cocktails for routine evaluation of problematic prostate specimens.

Testicular hilum and vascular invasion predict advanced clinical stage in nonseminomatous germ cell tumors

Clinical staging is a critical step in the management of testicular germ cell tumors. Up to one-third of nonseminomatous germ cell tumors of the testis present with metastatic disease (clinical stages II and III). We investigated the predictors of metastatic disease at presentation in a cohort of 148 consecutive nonseminomatous germ cell tumors of the testis, over a 10-year period. The following clinical and pathologic features were evaluated: age, tumor size, dominant tumor histology, coagulative necrosis, vascular invasion, rete testis invasion and tumor extension into tunica vaginalis, hilar soft tissue, epididymis, or spermatic cord. Studied parameters were correlated with the clinical stage at presentation. Of the 148 patients with nonseminomatous germ cell tumors of the testis, 94 (63%) were clinical stage I, 26 (18%) were stage II, and 28 (19%) were stage III at presentation. Mean patient age was 31 years (range, 17–83). Mean tumor size was 4.1 cm (range, 0.6–19). On univariate analysis, the following parameters showed statistically significant association with the advanced clinical stage at presentation: vascular invasion (P<0.001), rete testis invasion (P<0.001), hilar soft tissue invasion (P<0.001), epididymis invasion (P=0.005), spermatic cord invasion (P=0.005), and coagulative necrosis (P=0.062). On multivariate analysis, only vascular invasion (P=0.011) and invasion into the rete testis and the hilar soft tissues (P=0.007 and P=0.017, respectively) demonstrated significant association with advanced clinical stage at presentation. We conclude that in addition to vascular invasion, tumor invasion into the hilum (rete testis or hilar soft tissue) is also strongly associated with metastatic disease at presentation and should be part of the routine pathology reporting.