Stromal invasion pattern identifies patients at lowest risk of lymph node metastasis in HPV-associated endocervical adenocarcinomas, but is irrelevant in adenocarcinomas unassociated with HPV.

OBJECTIVE: The Silva invasion pattern-based classification system stratifies endocervical adenocarcinomas (ECAs) into 3 categories corresponding to risk of metastasis and recurrence, but has only been evaluated for HPV-associated ECAs of usual type. We examined whether the Silva system is applicable to all endocervical adenocarcinomas, especially those not associated with HPV. METHODS: Complete slide sets from 341 surgical specimens of ECA were collected from 7 institutions worldwide. All specimens were associated with clinical records covering at least 5 years of follow-up. Tumors were classified as HPV-associated (HPVA) or not (NHPVA) by both morphology and detection of HPV using in situ hybridization. Recurrence and survival were analyzed by multivariate Mantel-Haenszel methods. RESULTS: Most specimens (292; 85.6%) were HPVA, while 49 (14.3%) were NHPVA. All NHPVAs were Silva pattern C, while 76.0% of HPVAs were pattern C, 14.7% pattern A, and 9.3% pattern B. Including both HPVAs and NHPVAs, lymphovascular invasion (LVI) was detected in 0% of pattern A, 18.5% of pattern B and 62.6% of pattern C cases (p < 0.001). None of the pattern A or B cases were associated with lymph node metastases (LNM), in contrast to pattern C cases (21.8%). Among patients with Silva pattern C ECA, those with HPVA tumors had a lower recurrence rate and better survival than those with NHPVA; however, when adjusted for stage at diagnosis, the difference in recurrence and mortality was small and not statistically significant. CONCLUSIONS: Application of the Silva system is only relevant in HPVA cervical adenocarcinoma.

Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples.

AIM: This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide. METHODS: We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16(INK4a) expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance. RESULTS: HPV DNA was detected in 74% (95% confidence interval (CI): 70-78%) of invasive cancers and in 96% (95% CI: 92-98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16(INK4a) overexpression was found in 87% of HPV DNA positive vaginal cancer cases. CONCLUSIONS: HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts.

Overexpression of hypoxia-inducible factor 1 alpha impacts FoxP3 levels in mycosis fungoides--cutaneous T-cell lymphoma: clinical implications.

Mycosis fungoides (MF) is the most common variant of primary cutaneous T-cell lymphoma, and decreased forkhead box P3 (FoxP3) expression has been reported in MF late stages. Hypoxia-inducible factor 1 alpha (HIF-1α) may regulate FoxP3 expression; however, it is unknown whether HIF-1α is expressed in the CD4(+) T cells of MF patients and how it could affect the expression of FoxP3. Therefore, we evaluated the expression of HIF-1α and FoxP3 in CD4(+) T cells obtained from the skin lesions of MF patients. We found increased cell proliferation and an increase in CD4(+) T cells with an aberrant phenotype among early stage MF patients. HIF-1α was overexpressed in these CD4(+) T cells. In addition, we found a decrease in the percentage of FoxP3(+) cells both in the skin of MF patients, when compared with control skin samples, and with disease progression. In addition, a negative correlation was established between HIF-1α and FoxP3 expression. Skin HIF-1α expression in MF patients correlated with the extent of the affected area and increased with the disease progression. Finally, we showed that ex vivo inhibition of HIF-1α degradation increases the percentage of FoxP3(+) T cells in skin lesions. Our results suggest that overexpression of HIF-1α affects the levels of FoxP3 in MF patients, which could have relevant implications in terms of disease outcome.

Review of renal carcinoid tumor with focus on clinical and pathobiological aspects.

Renal carcinoid tumor is a rare neoplasm. In this article, we review this neoplasm with a focus on clinical and pathobiological aspects. The majority of patients present in the fourth to seventh decades, but there is no gender predilection. Clinically, patients with renal carcinoid tumor frequently present with abdominal, back or flank pain. This tumor is occassionally associated with horseshoe kidney and/or mature cystic teratoma located in the kidney. Macroscopically, these tumors are well demarcated with a lobulated appearance and yellow or tan-brown color cut surface. Microscopically, these tumors are composed of monomorphic round to polygonal cells with granular amphophilic to eosinophilic cytoplasm. Tumor cells are arranged in trabecular, ribbon-like, gyriform, insular, glandular and solid patterns. The nuclei are round to oval and with evenly distributed nuclear chromatin, frequently with a "salt and pepper"-pattern. Immunohistochemically, tumor cells demonstrate immuno-labeling for chromogranin A and synaptophysin. Ultrastructurally, the neoplastic cells contain abundant dense core neurosecretory granules. In previous genetic studies, abnormalities of chromosomes 3 or 13 have been reported. The clinical behavior of renal carcinoid tumors is variable, but is more indolent than most renal cell carcinomas. Further investigations are warranted in order to elucidate the critical genetic abnormalities responsible for the pathogenesis of this rare entity in renal neoplastic pathology.

[Clinicopathologic characteristics of 127 cases of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) studied in an oncology hospital]. / Características clínico-patológicas de 127 casos de neoplasias neuroendocrinas del aparato gastrointestinal y páncreas (NNE-GEP) estudiadas en un hospital de oncología.

BACKGROUND: Neuroendocrine tumors (NETs) present all along the length of the gastrointestinal (GI) tract, from the esophagus to the anus, and they also present in the pancreas. AIMS: To classify NETs according to the WHO 2010 criteria and to evaluate their anatomic distribution and clinicopathologic characteristics. MATERIAL AND METHODS: A search was carried out in the hospital pathology archives of all the cases diagnosed with carcinoid tumor and neuroendocrine carcinoma of the GI tract and pancreas studied over a period of 11 years (1999-2010). The cases were reclassified according to the WHO 2010 criteria. The clinical case records of each patient were reviewed. RESULTS: The study group was made up of 127 cases (68 men; 59 women). Age ranged from 24 to 85 years with a median of 52 years. A total of 113 (89.00%) tumors occurred in the GI tract and 14 (11.00%) in the pancreas. Tumor size varied from 0.4cm to 9cm (median: 2.5cm). GI tumor histologic grades were: 54.00% grade 1; 31.00% grade 2; and 15.00% grade 3. Pancreatic tumor histologic grades were: 43.00% grade 1; 36.00% grade 2; and 21.00% grade 3. Ki-67 overexpression was correlated with tumor grade (22.00% grade 3 vs 2.50% grade 1). CONCLUSIONS: Histologic grade of the gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is one of the most important prognostic factors. The term carcinoid should be eliminated because it does not reflect the biological behavior of these tumors.

BIK/NBK gene as potential marker of prognostic and therapeutic target in breast cancer patients

PURPOSE: The purpose of this study is to determine the association between the BIK/NBK gene expression and estrogen receptor alpha expression. MATERIALS AND METHODS: We determined the association of BIK/NBK gene expression by real time quantitative reverse transcription polymerase chain reaction and estrogen receptor alpha expression by immunohistochemistry in samples of breast cancer tissue. RESULTS: We found a statistically significant correlation of BIK/NBK gene expression with the estrogen receptor alpha expression (ρ = 0.751, p = 0.004). For verify differences of BIK/NBK gene expression among ERα+ and ERα- breast cancer tissues, Mann-Whitney U test was performed, obtaining significant differences. CONCLUSIONS: BIK/NBK gene expression may have important clinical implications and provide predictive, prognostic or therapeutic marker in breast cancer patients according to the estrogen receptor alpha expression (AU)

Immunophenotypic profile of biomarkers related to anti-apoptotic and neural development pathways in the Ewing's family of tumors (EFT) and their therapeutic implications.

BACKGROUND: Ewing's family of tumors (EFT) comprises a broad spectrum of tumors composed of primitive committed cells with neuroectodermal capacity. The degree of neural differentiation within EFT, as measured with morphological features and expression of neural markers, delimits two members: Ewing's sarcoma (ES) and peripheral primitive neuroectodermal tumor (pPNET). Molecules such as c-kit and its ligand (Stem cell factor, SCF), CD95 (FAS), CD95L (FASL), IGF-IR, protect EFT cells from apoptosis, whereas c-erb-B2, erythropoietin (EPO) and its receptor (EPO-R) participate in the maturation of primitive committed neuroectodermal cells and in the normal embryonal brain development. The aim of the present study was to analyse the expression of these molecules in paraffin-embedded material from a series of EFT. MATERIALS AND METHODS: Forty-five cases of EFT (23 typical ES, 4 atypical and 18 pPNET) were analysed following the immunohistochemical LSAB method, with antigen retrieval heating using an autoclave, citrate buffer pH 6.0 and the following primary antibodies: FAS (APO-CD 95), FAS-L, c-kit, SCF, IGF-IR and c-erbB2. The expression was evaluated independently by three of the authors and the final score (0 to 3+) was based on the intensity and percentage of positively stained cells. In a second cooperative analysis, tissues from 30 cases of EFT (15 typical, 3 atypical and 12 PNET) were immunostained with EPO and EPO-R. RESULTS: High expression of c-kit/SCF (2+, 3+) was detected in 28/45 cases of EFT (62.2%), whereas FAS-FAS-L and IGF-IR were observed in 16/45 (37.7%) and 9/45 (20%), respectively. Regarding the neuroectodermal pathway, membranous and cytoplasmic expression of c-erb-B2 was observed in 9/45 (20%) EFT, regardless of the morphological and immunohistochemical expression of conventional neural markers. High expression of EPO and EPO-R was observed in 20/30 EFT (66.6%). CONCLUSION: C-kit/SCF and EPO/EPO-R seem to participate in the pathway of anti-apoptotic and proliferative advantage, while c-erb-B2 does not play an important role in the neuroectodermal differentiation pathway in EFT cells.

Tumor size as predictor of microinvasion, invasion, and axillary metastasis in ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS) represents a small number of cases in countries with inadequate breast cancer screening programs, and in the majority of cases is diagnosed as a palpable lump. It has been proposed that DCIS with palpable lump > or = 2.5 cm can be associated with microinvasion or invasive carcinoma and risk of axillary metastasis. The purpose of the present study is to evaluate incidence of microinvasion, invasion, and the role of lymphatic mapping and sentinel lymph node biopsy in DCIS > or = 2.5 cm. We conducted a retrospective analysis of patients with histologically proven incisional, excisional, or core biopsy of DCIS lump > or = 2.5 cm at a tertiary-care hospital. All patients underwent lymphatic mapping with sentinel lymph node biopsy.A total of 24 patients were included with average tumor size of 4 cm (range, 2.5-6 cm); 29% had microinvasive and 12.5% had invasive disease, three patients (12.5%) had positive sentinel lymph node, all had micrometastasis, and no metastasis were found in non-sentinel lymph nodes. Incidence of microinvasion and invasion were directly related with tumor size (10% for DCIS tumor size of 2.5-3.5 cm, 57% for 3.6-4.5 cm, and 71% for tumors between 4.5 and 6 cm). In addition, axillary metastasis incidence had a direct relationship with tumor size. (0% in 2.5-3.5-cm tumor size, 14% for 3.6-4.5 cm, and 28% in DCIS between 4.6 and 6.0 cm). The present study shows high incidence of microinvasion and invasion in DCIS diagnosed in tumors > or = 2.5 cm and supports the importance of axillary evaluation in patients with tumors >3.5 cm by means of lymphatic mapping and sentinel lymph node biopsy.

Chromophobe renal cell carcinoma with microcystic and adenomatous arrangement and pigmentation--a diagnostic pitfall. Morphological, immunohistochemical, ultrastructural and molecular genetic report of 20 cases.

We present clinical, morphological, immunohistochemical, ultrastructural and molecular genetic features of 20 cases of a peculiar form of chromophobe renal cell carcinoma (CRCC) with morphology differing from that of conventional CRCC. Microscopically, the typical features of the tumors were microcystic arrangement and formation of adenomatous structures. Microcystic areas were composed of smaller eosinophilic and bigger pale cells having cytological appearance typical of conventional CRCC. Cytological features of the adenomatous structures were mostly different from those of conventional CRCC. They had a typical columnar arrangement with nuclei positioned at the base of the glandular structures and a small amount of a deeply eosinophilic cytoplasm often endowed with brush border facing the lumen of the glands. In addition, all the tumors showed a brown pigmentation. The pigmentation was located mostly extracellularly, where it formed pools of heavy deposits. Microscopic calcifications present in all cases formed psammoma bodies or else the calcifications were more extensive and amorphous in shape. Ultrastructurally, the cells showed features characteristic of CRCC: typical cytoplasmic vesicles were 100-700 nm in size and mitochondria had tubulovesicular, lamellar or circular cristae. Some tumor cells contained dark, variously sized electron-dense pigment granules. Neither melanosomes nor membrane-bound neurosecretory granules were seen. Using fluorescence in-situ hybridization probes for chromosomes 1, 2, 6, 10, 13, 17 and 21, the tumors revealed massive loss of tested chromosomes typical for conventional CRCC. Monosomy of chromosomes 1, 2, 6, 10, 13 and 21 was found in 100, 36, 91, 82, 82, 82 and 64% of cases, respectively. None of the cases showed mutation of exons 9, 11, 13 and 17 of the c-kit gene. The important feature of pigmented microcystic chromophobe renal cell carcinoma is a relatively benign biological behavior and the absence of distant metastases and sarcomatoid transformation.

[Spindle cell and cuboidal renal cell carcinoma (loopoma). 10 case reports]. / Vretenobunecný a kuboidální renální karcinom (loopom). Popis 13 prípadu.

BACKGROUND: Current classification systems of neoplasms arising from renal parenchyma distinguish 5 categories of renal cell carcinoma (RCC), i.e. conventional RCC, papillary RCC, chromophobe RCC, collecting duct/medullary RCC and unclassified RCC. We present 13 cases of unusual and unclassified spindle and cuboidal renal cell carcinomas. METHODS AND RESULTS: The studied group consisted of 13 patients (7 men and 6 women). They ranged in age from 22 to 65 years (mean 57.3). Generally, the tumours were well circumscribed and confined to the kidney, whitish to grey on section with a diameter 4.5-13 cm (mean 8.6 cm). One patient was investigated for loin pain and nocturia. Three patients had staghorn nephrolithiasis and vague sonographic findings in renal parenchyma. In one patient the renal tumour was found when examined on follow-up examination for prostatic adenocarcinoma. None of our patients was known to have elevated levels of parathyroid hormone due to hyperplasia, adenoma or carcinoma of the parathyroid gland. Clinical follow-up of the patients ranged from 9 months to 8 years (mean 2.3 years). Microscopically, the tumours were composed of two main populations of cells: flattened, spindle cells with sparse cytoplasm and small cuboidal cells with clear to light eosinophilic cytoplasm. Eight patients are currently well without signs of recurrence or metastasis, one had metastasis in the regional lymph node at the time of nephrectomy, one died of unrelated cause, and three were lost to follow-up. CONCLUSIONS: We present 13 cases of unclassified RCC. Our cases were histologically, immunohistochemically and ultrastructurally similar to the hitherto reported case reports of this variant of RCC. It is obvious, that that variant of RCC should be recognised as a new subtype of RCC.

Metastases to the breast.

AIM: The aim of this study was to report the clinico-pathological features of a series of patients with metastatic neoplasms to the breast. METHODS: A 10-year archive of surgical material was reviewed. A search was performed on all 10,650 breast neoplastic cases in the files of the Pathology Department from 1990 to 2000. RESULTS: There were 22 women and two men. The most common primary sites for solid tumours were cutaneous melanoma and ovarian carcinoma. Two of the 24 patients had no prior history of malignant disease. There was a solitary nodule in 17 cases; in seven cases there were multiple lesions in the same breast. Sixteen patients had a rapidly fulminating course and died of disease. Six patients are alive with disease and two patients were lost to follow-up. CONCLUSION: Recognition of these lesions as being metastatic may pre-empt radical surgery.

[Primary sterility and cervical pregnancy. A case report]. / Esterilidad primaria y embarazo cervical. A propósito de un caso.

Fortunately cervical pregnancy, an ectopic gestation that frequently represents obstetric urgency, is a rare entity. We present here the case of a woman who developed cervical pregnancy despite no risk factor associated with ectopic pregnancy was identified. The patient came to the office because of primary sterility of 4 years of evolution. Among her background she reported previous cervical surgery due to benign pathology. She reached pregnancy after medical and surgical treatment. In the week eleven of gestation, the patient presented to the hospital with clinical symptoms of abortion. An ultrasound revealed abdominal pregnancy. Laparotomy was "white", cervix was found enlarged with the external orifice closed, suggesting cervical pregnancy. Conservative treatment consisted in cervical evacuation, endometrial curettage and vaginal tampon. She evolved satisfactorily. We do not know about any previous report of cervical-pregnancy associated with cervical surgery and sterility. We also recognize the need to increase the number of similar cases to generalize results. Thus, it is important to highlight in this case the absence of known risk factors for cervical pregnancy and the background of cervical surgery and sterility. Therefore, we recommend to search for antecedents of cervical surgery and sterility when cervical pregnancy is suspected.

Esterilidad primaria y embarazo cervical. A propósito de un caso / Primary sterility and cervical pregnancy. A case report

Fortunately cervical pregnancy, an ectopic gestation that frequently represents obstetric urgency, is a rare entity. We present here the case of a woman who developed cervical pregnancy despite no risk factor associated with ectopic pregnancy was identified. The patient came to the office because of primary sterility of 4 years of evolution. Among her background she reported previous cervical surgery due to benign pathology. She reached pregnancy after medical and surgical treatment. In the week eleven of gestation, the patient presented to the hospital with clinical symptoms of abortion. An ultrasound revealed abdominal pregnancy. Laparotomy was "white", cervix was found enlarged with the external orifice closed, suggesting cervical pregnancy. Conservative treatment consisted in cervical evacuation, endometrial curettage and vaginal tampon. She evolved satisfactorily. We do not know about any previous report of cervical-pregnancy associated with cervical surgery and sterility. We also recognize the need to increase the number of similar cases to generalize results. Thus, it is important to highlight in this case the absence of known risk factors for cervical pregnancy and the background of cervical surgery and sterility. Therefore, we recommend to search for antecedents of cervical surgery and sterility when cervical pregnancy is suspected.

Sporadic type composite pheochromocytoma with neuroblastoma: clinicomorphologic, DNA content and ret gene analysis.

Composite pheochromocytomas (CP) account for only 3% of all pheochromocytomas. We analyzed the clinical, immunohistochemical, ultrastructural, DNA content, and 634 ret mutation features in a 56-year-old Mexican woman with CP localized in the right adrenal gland and associated to a blood pressure of 140/90 mmHg. Clinical symptoms were absent after surgery. The tumor showed pheochromocytoma and neuroblastoma components. This dual phenotype was supported by light microscopy and corroborated by immunohistochemistry and ultrastructural findings. Flow cytometric analysis showed that both components were diploid. A genetic mutational analysis of the ret oncogene in exon 11 showed no 634 mutation. This case demonstrates the indolent behavior of neuroblastoma associated to a sporadic-type CP in an adult patient.

Leiomyoma of the urethra in a Mexican woman: a rare neoplasm associated with the expression of estrogen receptors by immunohistochemistry.

BACKGROUND: Leiomyoma of the female urethra is a rare condition, although it can occur anywhere along the genitourinary tract. METHODS: We report on a 22-year-old woman found to have a urethral mass detected in our hospital delivery room. Examination showed a 6 X 5-cm mass at the urethral meatus. RESULTS: Pathologic examination revealed urethral leiomyoma. Immunohistochemistry confirmed leiomyoma with positive staining for vimentin, desmin, and actin. Immunoreactivity for estrogen receptors was also detected. CONCLUSIONS: Because this lesion was discovered while the patient was pregnant and it showed immunoreactivity for estrogen receptors, it is suggested that increased estrogen levels could accelerate smooth muscle growth.

[Laryngeal plasmacytoma]. / Plasmocitoma de laringe.

Solitary plasmocytoma is a rare presentation of plasma cell dyscrasia. About 1% od the patients can present with a extramedullary plasmocytoma; although bone presentation is the most frequent, in some cases, soft tissue can be affected. Radiotherapy remain as the election treatment. A case of primary plasmocytoma of the larynx is presented. The patient is alive after radiotherapy. Discussion about the clinical differentiation and also a review of the literature is present.

[Nephrogenic adenoma of the urinary bladder. A lesion that can be confused with carcinoma. Report of 4 cases]. / Adenoma nefrogénico de la vejiga urinaria. Una lesión que puede ser confundida con carcinoma. Reporte de cuatro casos.

Nephrogenic Adenoma (NA) was first illustrated in 1949 by Davis, who described a case he interpreted as a "hamartoma". One year later Friedman and Kuhlenbeck described eight further examples in detail and named this lesion nephrogenic adenoma. This process is generally accepted to be metaplastic. At cystoscopy and on microscopic examination nephrogenic adenoma may simulate a neoplasm. The clinical and pathologic findings in four patients are described. The patients were two women and two men 20-60 years of age. All of them had a history of some inciting injury (infection/calculus). The four cases were initially misdiagnosed as a carcinoma. Several features of NA may cause particular diagnostic difficulty. Tiny tubules may simulate signet ring cells, the haphazard distribution of the tubules or single cell growth may also simulate the appearance of an invasive adenocarcinoma. A variety of clinical and pathologic differences should enable the distinction of these lesions. Although this is occasionally difficult. An emphasis here is placed on the diagnostic problems that they may pose for the surgical pathologist. Clinicians and pathologists should be aware about this type of lesions in order to avoid pitfalls in the diagnosis and treatment of them.

Intrarenal schwannoma: a report of four cases including three cellular variants.

Renal schwannomas are extraordinarily rare neoplasms; only six have been reported, the majority of which occurred in the renal pelvis. We report the clinical and pathologic features of four additional cases. The resected kidney in all patients contained a well-demarcated, yellow-tan, smooth, and bulging intraparenchymal tumor (mean size, 9.7 cm; range, 4 to 16 cm). Microscopically, three cases were classified as cellular schwannomas, and one was a usual-type schwannoma, with degenerative nuclear atypia. By immunohistochemistry, all tumors were strongly S-100 protein positive and negative for pan-cytokeratin, CD57, smooth muscle actin, desmin, and CD34. Epithelial elements were not noted in the tumors, and there was no history of any clinical syndromes in these patients. Analysis of the four cases showed the mean age at presentation to be 47 years (range, 18 to 84 years), with no sex predisposition (two men, two women). Most patients were asymptomatic, and all received a diagnosis of renal cell carcinoma and treated as having such. Recognition and awareness of these rare, benign tumors will assist in the differential diagnosis of spindle cell tumors of the kidney and prevent their misdiagnosis as sarcomatoid carcinomas of the kidney or renal sarcomas. Our study, the largest series to date of renal schwannomas, demonstrates a predilection for the cellular variant in the kidney, documents that these tumors may present in the nonhilar region of the kidney, and provides clinical evidence of their benign biologic behavior.