Ondrej Ondic

Spindle and cuboidal renal cell carcinoma, a tumour having frequent association with nephrolithiasis: report of 11 cases including a case with hybrid conventional renal cell carcinoma/ spindle and cuboidal renal cell carcinoma components

Aims:  We present the largest series of an unclassified subtype of renal cell carcinoma, which seems to be a distinct morphological entity and which is sometimes designated as spindle and cuboidal renal cell carcinoma.

Fumarate Hydratase-deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyoma: defined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FH-deficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FH-deficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations.

Cystic and necrotic papillary renal cell carcinoma: prognosis, morphology, immunohistochemical, and molecular-genetic profile of 10 cases.

Conflicting data have been published on the prognostic significance of tumor necrosis in papillary renal cell carcinoma (PRCC). Although the presence of necrosis is generally considered an adverse prognostic feature in PRCC, we report a cohort of 10 morphologically distinct cystic and extensively necrotic PRCC with favorable biological behavior. Ten cases of type 1 PRCC with a uniform morphologic pattern were selected from the 19 500 renal tumors, of which 1311 were PRCCs in our registry. We focused on precise morphologic diagnosis supported by immunohistochemical and molecular-genetic analysis. Patients included 8 men and 2 women with an age range of 32-85 years (mean, 62.6 years). Tumor size ranged from 6 to 14 cm (mean, 9.4 cm). Follow-up data were available in 7 patients, ranging from 0.5 to 14 years (mean, 4 years). All tumors were spherical, cystic, and circumscribed by a thick fibrous capsule, filled with hemorrhagic/necrotic contents. Limited viable neoplastic tissue was present only as a thin rim in the inner surface of the cyst wall, consistent with type 1 PRCC. All cases were positive for AMACR, OSCAR, CAM 5.2, HIF-2, and vimentin. Chromosome 7 and 17 polysomy was found in 5 of 9 analyzable cases, 2 cases demonstrated chromosome 7 and 17 disomy, and 1 case showed only chromosome 17 polysomy. Loss of chromosome Y was found in 5 cases, including 1 case with disomic chromosomes 7 and 17. No VHL gene abnormalities were found. Papillary renal cell carcinoma type 1 can present as a large hemorrhagic/necrotic unicystic lesion with a thick fibroleiomyomatous capsule. Most cases showed a chromosomal numerical aberration pattern characteristic of PRCC. All tumors followed a nonaggressive clinical course. Large liquefactive necrosis should not necessarily be considered an adverse prognostic feature, particularly in a subset of type 1 PRCC with unilocular cysts filled with necrotic/hemorrhagic material.

Borderline papillary serous tumor of the fimbriated end of the fallopian tube with peritoneal implants

Diagnosis of Borderline papillary serous tumor of the fallopian tube was comprehensively established by Zheng in 1996 supported mostly by a histological similarity to its ovarian counterpart. It is a very rare entity with eight cases published so far and the ninth case described here as a 41‐year‐old woman presented with non‐specific lower abdominal pain, dyspareunia and dysuria. Left adnexal mass was identified and she was operated on. It turned out the tumor was attached exclusively to the left tube, with no connection to any of the surrounding structures and with histology of borderline serous tumor with non‐invasive implants in the left and right ovary and visceral peritoneum. Reviewing available data on genetics of these tumors there was diploid status in one examined tumor, and in our case no mutations of KRAS, BRAF and p53 genes were found. Histomorphology remains the mainstay of diagnosis and staging operation is the mainstay of patient management. Prognosis is uncertain with a 6‐year survival documented in one case.

Origin of cystic squamous cell carcinoma metastases in head and neck lymph nodes: Addition of EBV testing improves diagnostic accuracy

Most cases of cystic squamous cell carcinoma (SCC) metastases in the upper neck are associated with an oropharyngeal primary, namely human papillomavirus (HPV)-associated SCC arising in the palatine or lingual tonsil. A retrospective study was performed on 22 patients who presented with cystic head and neck SCC metastases. The purpose of the study was to find out whether histological characteristics, p16 protein expression, HPV and Epstein-Barr virus (EBV) status could be useful in predicting the localization of the primary tumor. The primary site was identified in 20 of 22 patients and included the oropharynx in 14 patients (63.6%), the nasopharynx in 3 patients (13.6%), the lungs in 2 cases (9%), and the skin of the auricle in one case (4.5%). No primary was found in two patients (9%). Sixteen of 17 cases (94.1%) originating in Waldayers ring (oropharynx and nasopharynx), and both cases with an unknown primary showed morphology of non-keratinizing SCC or non-keratinizing SCC with maturation. All tumors with oropharyngeal primary and both cases with unknown primary showed diffuse p16 staining and presence of HPV DNA. All three cystic metastases of nasopharyngeal carcinoma were EBV-positive and p16/HPV-negative. In contrast, cutaneous and pulmonary metastases showed morphology of a well differentiated keratinizing SCC and poorly differentiated keratinizing SCC, respectively, and were HPV/EBV-negative. We confirmed that cystic SCC lymph node metastases of the head and neck region are strongly associated with the occult primary localized in the oropharynx. The oropharyngeal origin should always be corroborated by p16 immunohistochemistry and HPV-specific testing because SCC arising in other sites, such as nasopharynx, skin or lungs may manifest with cystic neck metastases as well. Addition of EBV testing in p16/HPV-negative cases can disclose the nasopharyngeal origin of the cystic neck metastases in a subset of cases.

Programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) expression in fumarate hydratase-deficient renal cell carcinoma

Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and aggressive tumor affecting mostly younger patients. This is the first study to assess the expression of programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) in FH-RCC. Formalin-fixed paraffin-embedded samples from 13 FH-RCCs collected in an international multi-institutional study, were evaluated by immunohistochemistry (IHC) for PD-1/PD-L1 reactivity in tumor cells and tumor infiltrating lymphocytes (TILs). PD-1/PD-L1 expression was further evaluated by qPCR. By IHC, PD-1 was negative in tumor cells in all 13 cases. PD-L1 was positive in tumor cells in 2/13 cases, weak positive in 7/13, and negative in 4/13 cases, respectively. In TILs, PD-1 was positive in 1/13, weak positive in 3/13, and negative in 9/13 cases. In TILs, PD-L1 was weak positive by IHC in 5/13, and negative in 8/13 cases, respectively. qPCR confirmed the result for 2 of 3 IHC weak positive PD-1 samples. Of 7 IHC weak positive samples (in tumor cells), PD-L1 mRNA was detected in all 7 tumors. The majority of FH-RCCs did not express PD-1/PD-L1 by IHC, which was confirmed by molecular analysis. PD-1/PD-L1 expression in FH-RCC is restricted to a proportion of cases which may benefit from targeted therapies.

Bizarre cell dysplasia of the cervix

The aim of this study was the characterization of a new subtype of high‐grade cervical squamous intraepithelial lesion (HSIL) with enlarged cells containing bizarre nuclei: so‐called bizarre cell dysplasia (BCD).

Mixed Epithelial and Stromal Tumor of the Kidney: Mutation Analysis of the DICER 1 Gene in 29 Cases.

Cystic nephroma (CN) and mixed epithelial stromal tumor (MEST) of the kidney have been considered as synonymous terms describing a single nosologic entity in adult patients. Cystic nephroma in pediatric patients (PCN) is, apparently, a completely different nosologic entity. Although the presence of DICER 1 mutations is well established in PCN, nothing is currently known about the DICER 1 gene status in adult MEST/CN. About 33 cases of MEST/CN were selected from the Plzen Tumor Registry; 4 cases were later excluded from the study due to low DNA quality. About 28 of the studied tumors displayed a benign morphology, whereas 1 was diagnosed as a malignant MEST/CN with sarcomatoid differentiation of the stromal component. All 29 samples analyzed using polymerase chain reaction and direct sequencing, including the case with the malignant morphology, were negative for mutation in DICER 1 hot-spot codons 1705, 1709, 1809, 1810, 1813, and 1814. Our results show that MEST/CN has no relation to PCN on a molecular genetic level. On the basis of our findings and the established morphologic differences between PCN and MEST/CN, we conclude that the term CN should be used for pediatric cases only and should be avoided in adult cases of MEST.

Human Papillomavirus Infection and p16 Expression in Extragenital/Extraungual Bowen Disease in Immunocompromised Patients.

Abstract:An increased rate of second nonmelanoma skin cancers is found in immunocompromised patients. Epidemiological and molecular data implicate ultraviolet radiation as the major risk factor. In addition, there is increasing evidence supporting the role of human papillomavirus (HPV) in the pathogenesis of premalignant and malignant skin lesions in both immunocompetent and immunocompromised patients. In a retrospective cross-sectional study, the authors examined the expression of p16 by immunohistochemistry and the presence of mucosal (&agr;-genus) and cutaneous/epidermodysplasia verruciformis (&bgr;-genus) HPV DNA by polymerase chain reaction in 29 biopsy specimens of extragenital/extraungual Bowen disease (BD) from 24 Eastern European white immunocompromised patients. Furthermore, the author evaluated the association between the expression of p16 protein and the presence of HPV DNA. Among 25 specimens from 21 patients evaluable by polymerase chain reaction, HPV DNA was detected in 10 (40%) BD lesions from 9 patients. Beta-HPV predominated over alpha-HPV types. Among 29 immunohistochemically evaluable BD specimens, 22 lesions (∼76%) from 20 patients were scored as p16 positive. HPV DNA-positive and HPV DNA-negative lesions displayed the same proportion of p16 positivity (80%) and no correlation was found between the HPV DNA presence and the p16 expression status. Our pilot study demonstrated that &bgr;-HPV infections predominate in BD cases diagnosed among immunocompromised patients, although high- and low-risk mucosal (alpha) HPV genotypes may be detected in a minority of cases. In contrast to anogenital HPV-associated lesions, positive p16 expression is not a reliable marker of high-risk &agr;-HPV infection in BD cases, as it can be also detected in &bgr;-HPV infected and HPV-negative cases.

Low‐grade spindle cell proliferation in clear cell renal cell carcinoma is unlikely to be an initial step in sarcomatoid differentiation

Spindle cell proliferation within clear cell renal cell carcinoma (ccRCC) is usually considered as a sarcomatoid differentiation. Low‐grade spindle cell proliferation (LG‐SCP) in ccRCC was first described in 2001. This phenomenon is not common and can pose diagnostic challenges, particularly in core biopsies. The aim of this study was to describe morphological, immunohistochemical and molecular characteristics of ccRCCs with LG‐SCP.