Hobnail Cells Research Articles

Diffuse sclerosing variant of papillary thyroid carcinoma: a study of fine needle aspiration cytology in 20 patients

A diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is a rare variant and reports describing the cytological findings are few. We studied 24 cytological samples from thyroid fine needle aspirates of 20 patients with DSV-PTC. The specimens were taken from 14 non-nodular lesions and 10 nodules. All aspirates taken from both non-nodular lesions and nodules had sufficient cellularity. The carcinoma cells frequently (70-100%) appeared as solid cell balls and hollow balls, and showed a hobnail pattern, squamous differentiation, septate cytoplasmic vacuoles and large unilocular vacuoles. Most of the carcinoma cells seem to be taken from the lumen of dilated lymph vessels. Ground glass nuclear chromatin, intranuclear cytoplasmic inclusions and grooved nuclei were infrequent (50% or less). In the background, a large number of lymphocytes and abundant psammoma bodies were almost always seen. Cytological findings of DSV-PTC are as follows: (1) solid cell balls and/or hollow balls containing lymphocytes; (2) hobnail cells; (3) septate cytoplasmic vacuoles; (4) large unilocular vacuoles; (5) squamous differentiation; (6) abundant psammoma bodies; (7) lymphocytic background; and (8) the absence or relative lack of characteristic nuclear features of papillary carcinoma. When DSV-PTC is suspected by ultrasound examination, the aspiration cytology from a non-nodular area of the thyroid can led us to the diagnosis of the variant.

Tubulocystic carcinoma of the kidney: a histologic, immunohistochemical, and ultrastructural study

Tubulocystic carcinoma of the kidney (TCCK) is a tumor entity, which is not yet included in the WHO classification of renal tumors. The histogenesis of this neoplasm is uncertain. This study was undertaken to determine (1) the incidence of TCCK and (2) immunohistochemical and ultrastructural characteristics of those tumors that qualify as TCCK by the current definitions. From January 1, 2003 to December 31, 2012, a total of 615 renal cell carcinomas (RCCs) were seen by the Department of Pathology, University of Maryland Medical Center. Four TCCKs were identified (4/615, <1%). TCCK is a distinctive group of kidney tumors with a male predominance and noteworthy macroscopic spongy appearance. Microscopically, the tumors were composed of tubules and cysts lined by a single layer of eosinophilic, columnar, cuboidal, flat, or hobnail cells with large nuclei and prominent nucleoli separated by a thin fibrotic stroma. In all TCCKs, the majority of neoplastic cells showed immunohistochemical (CD10(+), RCC(+), vimentin(+), and AMACR(+)) and ultrastructural (abundant long brush border microvilli) characteristics of proximal renal tubules. In few cells, the microvilli were shorter and sparse with cytoplasmic interdigitation analogous to intercalated cells of the collecting ducts. Focal positivity for BerEP4 (a marker preferentially expressed in distal renal tubules) was also noted. The major differential diagnostic considerations are oncocytoma, multilocular cystic renal cell carcinoma, and cystic nephroma/mixed epithelial and stromal tumor of the kidney. TCCK seems to have a favorable prognosis. In the current series, none of the patients had local recurrence or metastatic disease.

Clear Cell Adenocarcinoma of the Renal Pelvis in a Male Patient

Carcinoma of the renal pelvis is an uncommon renal neoplasm. Clear cell adenocarcinoma in the urinary tract is rare and has a histomorphology resembling that of the female genital tract. We herein present a case of clear cell adenocarcinoma of the renal pelvis, which is the first example in a male patient to our knowledge. A 54-year-old man presented with right flank pain. The tumor was associated with renal stones and hydronephrosis and invaded into the peripelvic fat tissue with regional lymph node metastasis. The patient died of metastatic disease six months postoperatively. Histologically, the tumor showed complex papillary architecture lined with clear and hobnail cells. Clear cell adenocarcinoma of the renal pelvis may pose a diagnostic challenge on histological grounds, particularly in the distinction from renal cell carcinoma. The immunohistochemical stains could help confirm the diagnosis. Due to its rarity, an effective treatment regimen remains to be determined.

Mixed angiosarcoma, clear cell adenocarcinoma and mature teratoma elements in an ovarian tumor: A case report and literature review

Malignant transformation of a mature teratoma in the ovary is a rare event, with an approximate rate of only 1-2%. Here, we report an ovarian tumor with a unique combination of epithelial and non-epithelial malignant components, including mature teratoma elements. A 59 year-old postmenopusal woman underwent total hysterectomy and bilateral salpingo-oophorectomy to remove a huge solid mass of the right ovary. The ovarian tumor was 16 × 12 × 4.5 cm in dimensions, composed of red-brown and greyish-white tissue with several cystic areas. Microscopically, atypical cells immunopositive for both CD31 and CD34 formed irregular ectatic vascular patterns with a high MIB-1 labeling index in red-brown areas. In contrast, tubule-cystic and papillary structures were lined by HNF-1β-immunopositive atypical cuboidal and hobnail cells with clear cytoplasm in greyish-white areas. In addition, normal-looking epithelial and stromal components, including mature squamous, cuboidal and ciliated epithelial cells, and adipose tissues, were observed in red-brown areas, suggesting an ovarian tumor combining angiosarcoma, clear cell adenocarcinoma, and mature teratoma features. We could demonstrate identical X-chromosome inactivation patterns among all three components by human androgen receptor gene (HUMARA) assays, pointing to complex inter-relationships regarding their pathogenesis. These observations suggest that a malignant tumor composed of two characteristic phenotypes arose in mature teratoma.

Synchronous clear cell renal cell carcinoma and tubulocystic carcinoma: genetic evidence of independent ontogenesis and implications of chromosomal imbalances in tumor progression

Seven percent of renal cell carcinoma (RCC) cases are diagnosed as "unclassified" RCC by morphology. Genetic profiling of RCCs helps define renal tumor subtypes, especially in cases where morphologic diagnosis is inconclusive. This report describes a patient with synchronous clear cell RCC (ccRCC) and a tubulocystic renal carcinoma (TCRC) in the same kidney, and discusses the pathologic features and genetic profile of both tumors. A 67 year-old male underwent CT scans for an unrelated medical event. Two incidental renal lesions were found and ultimately removed by radical nephrectomy. The smaller lesion had multiple small cystic spaces lined by hobnail cells with high nuclear grade separated by fibrous stroma. This morphology and the expression of proximal (CD10, AMACR) and distal tubule cell (CK19) markers by immunohistochemistry supported the diagnosis of TCRC. The larger lesion was a typical ccRCC, with Fuhrman's nuclear grade 3 and confined to the kidney. Molecular characterization of both neoplasms using virtual karyotyping was performed to assess relatedness of these tumors. Low grade areas (Fuhrman grade 2) of the ccRCC showed loss of 3p and gains in chromosomes 5 and 7, whereas oncocytic areas displayed additional gain of 2p and loss of 10q; the high grade areas (Fuhrman grade 3) showed several additional imbalances. In contrast, the TCRC demonstrated a distinct profile with gains of chromosomes 8 and 17 and loss of 9. In conclusion, ccRCC and TCRC show distinct genomic copy number profiles and chromosomal imbalances in TCRC might be implicated in the pathogenesis of this tumor. Second, the presence of a ccRCC with varying degrees of differentiation exemplifies the sequence of chromosomal imbalances acquired during tumor progression.Virtual SlidesThe virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/1790525735655283

Cytologic Findings of Clear Cell Adenocarcinoma of the Urethra: A Case Report

Clear cell adenocarcinoma of the urethra is a rare disease entity with an uncertain histogenesis. Here, we present a case of primary clear cell adenocarcinoma of the female urethra with its cytological findings. A 54-year-old woman presented with a painless gross hematuria lasting 3 months. On vaginal sonography, there was a sausage-like, elongated mass in the urethra, measuring 3.8×4.3 cm. The voided urine cytology revealed small clusters of rounded or papillary cells. The necrotic debris and inflammatory cells were present within some clusters of tumor cells. These tumor cells were enlarged and had abundant clear or granular cytoplasm with cytoplasmic vacuoles. The nucleus was granular and contained vesicular chromatin with prominent nucleoli. The hobnail cells and hyaline globules were also present as in a histologic section. The histologic findings were compatible with clear cell adenocarcinoma. The tumor showed distinctive cytological features. Cytologically, however, it is necessary to make a differential diagnosis from other adenocarcinoma or high-grade urothelial carcinoma.

A cutaneous vascular neoplasm with hobnail microscopic morphology and unusual gross features

Vascular tumors are categorized into benign hemangiomas, frankly malignant angiosarcomas and tumors with intermediate biological behavior (hemangioendotheliomas). The latter group includes hemangioendotheliomas of the epithelioid, kaposiform, retiform and composite subtypes. Furthermore, a heterogeneous group of both benign and intermediate vascular tumors exhibits a peculiar hobnail cell morphology. This heterogeneous group encompasses hobnail hemangioma, retiform hemangioendothelioma, papillary intralymphatic angioendothelioma and a subset of angiosarcoma. We herein present a case of a cutaneous vascular neoplasm with hobnail morphology and unusual gross features.

Metastatic Clear Cell Adenocarcinoma of the Urethra in a Male Patient: Report of a Case

A 39-year-old white male presented with urinary hesitancy 2.5 years ago. He was referred to a urologist who performed cystoscopic evaluation and discovered a urethral mass with no abnormalities in the bladder. A staging positron emission tomography (PET) scan revealed fluorine-18 (F) fluorodeoxyglucose (FDG) uptake in a soft tissue prominence in the urethra and bilateral inguinal and iliac FDG-avid lymphadenopathy. Computed tomography (CT) of the hest also demonstrated several bilateral lung nodules. Needle biopsy f a left pelvic lymph node showed adenocarcinoma with micropapllary architecture (Figure 1A). Immunohistochemical analysis howed the carcinoma was positive for CK7 and CAM 5.2 and negtive for CK20, -fetoprotein, CDX-2, and prostate-specific antigen the immunostains are not shown). Sections from the subsequent ransurethral resection specimen of the urethral tumor showed an denocarcinoma with a tubulocystic, micropapillary, and solid archiecture (Figure 1B-D). The tumor had hobnail cells, clear and amhophilic cytoplasm, and high-grade nuclear atypia (Figure 1E). An

Glandular Odontogenic Cyst: Analysis of 46 Cases with Special Emphasis on Microscopic Criteria for Diagnosis

The glandular odontogenic cyst (GOC) is now a relatively well-known entity with recent reviews indicating over 100 cases reported in the English literature. The GOC's importance relates to the fact that it exhibits a propensity for recurrence similar to the odontogenic keratocyst, and that it may be confused microscopically with central mucoepidermoid carcinoma (CMEC). Numerous histopathologic features for the GOC have been described, but the exact microscopic criteria necessary for diagnosis have not been universally accepted. Furthermore, some of the microscopic features of GOC may also be found in dentigerous, botryoid, radicular, and surgical ciliated cysts. The purpose of this multicenter retrospective study is to further define the clinical, radiographic, and microscopic features of GOC, to determine which microscopic features may be helpful for diagnosis in problematic cases, to determine the most appropriate treatment, and to determine if GOC and CMEC share a histopathologic spectrum. In our series of 46 cases, the mean age at diagnosis was 51years with 71% of cases in the 5th-7th decades. No gender predilection was noted. 80% of cases occurred in the mandible, and 60% of the lesions involved the anterior regions of the jaws. Swelling/expansion was the most common presenting complaint, although some cases were asymptomatic. Radiographically, most cases presented as a well-defined unilocular or multilocular radiolucency involving the periapical area of multiple teeth. Some lesions displayed a scalloped border. Cases also presented in dentigerous, lateral periodontal, and "globulomaxillary" relationships. The canine area was a common location for maxillary cases. All cases were treated conservatively (enucleation, curettage, cystectomy, excision). Follow-up on 18 cases revealed a recurrence rate of 50% (9/18), with 6 cases recurring more than once (range of follow-up: 2months to 20years; average length of follow-up: 8.75years). The mean interval from initial treatment to first recurrence was 8years, and from first recurrence to second recurrence was 5.8years. Two cases recurred three times and the interval from second to third recurrence was 7years (exact interval only documented in one case). All cases exhibited eosinophilic cuboidal (hobnail) cells, a feature not specific for GOC, but necessary for diagnosis, in our opinion. Univariate analysis indicated several features that are most helpful in distinguishing GOC from GOC mimickers in problematic cases, including: (1) the presence of microcysts (P<0.0001); (2) epithelial spheres (P<0.0001); (3) clear cells (P=0.0002); (4) variable thickness of the epithelial cyst lining (P=0.0002); and (5) multiple compartments (P=0.006). Stratified analysis indicated that when microcysts are present, epithelial spheres and multiple compartments are still significant, and clear cells are marginally significant in distinguishing GOCs from GOC mimickers. The presence of microcysts (P=0.001), clear cells (P=0.032), and epithelial spheres (P=0.042) appeared to be most helpful in distinguishing GOC associated with an unerupted tooth from dentigerous cyst with metaplastic changes. There were no statistically significant differences microscopically between GOCs that recurred and those that did not. The presence of 7 or more microscopic parameters was highly predictive of a diagnosis of GOC in our series (P<0.0001), while the presence of 5 or less microscopic parameters was highly predictive of a non-GOC diagnosis (P<0.0001). Islands resembling mucoepidermoid carcinoma (MEC-like islands) were identified in the cyst wall of three cases, only one of which had follow-up (no evidence of disease at 74 mo.); therefore, at this time insufficient information is available to determine whether GOC and CMEC share a histopathologic spectrum or whether MEC-like islands in GOCs are associated with more aggressive or malignant behavior.

Anastomosing Hemangioma of the Genitourinary System

We describe 3 ovarian and 5 renal anastomosing hemangiomas. One manifested with polycythemia, others were incidental; none recurred. The mean patient age was 58 years. Three hemangiomas developed in end-stage renal disease. Tumors were well-demarcated, mahogany brown, spongy lesions measuring 0.1 to 5 cm. Tortuous large vessels fed and drained tightly packed anastomosing sinusoidal capillary channels. Four hemangiomas exhibited lobular architecture, central edema/hyalinization, and intravascular growth. Five cases had thrombosis, hemorrhage, and hemosiderin. One ovarian tumor induced stromal luteinization. Three tumors had foci of extramedullary hematopoiesis (one associated with polycythemia). Six cases demonstrated eosinophilic intracytoplasmic globules. Three cases included hobnail endothelial cells. Atypia was minimal and mitoses were absent in all cases. We find this vascular neoplasm unique for the genitourinary system. Despite selected features mimicking angiosarcoma, our data support its benign nature. The current study expands the gross and radiographic appearance, clinical aspects, and ultrastructure, with the first report of the lesion occurring in the ovary.

Diffuse Expression of PAX2 and PAX8 in the Cystic Epithelium of Mixed Epithelial Stromal Tumor, Angiomyolipoma With Epithelial Cysts, and Primary Renal Synovial Sarcoma

Over the past decade, 3 novel, typically cystic renal neoplasms have been described: angiomyolipoma with epithelial cysts (AMLEC), mixed epithelial stromal tumor (MEST), and primary renal synovial sarcoma (SS). In all 3 neoplasms, the nature of the cystic epithelium is not clear; some have postulated that the cysts represent cystically dilated, entrapped renal tubular epithelium, whereas an alternative interpretation is that the epithelium represents epithelial differentiation by the stromal component of the neoplasm. The latter is supported by the extrarenal location of the epithelium in some cases. PAX2 and PAX8 are tissue-specific transcription factors expressed primarily in the renal and Müllerian systems and also in Wolffian duct structures (such as seminal vesicle). Their expression has not been examined in these lesions. We performed PAX2 and PAX8 immunohistochemistry on representative sections of cases of AMLEC (8 cases), MEST (8 cases), and renal SS (3 cases). The relative percentage and intensity (none, weak, moderate, and strong) of nuclear labeling were evaluated in both the benign adjacent renal tubules and the lesion's epithelial cysts. In the benign kidney, distal convoluted tubules (DCTs) labeled strongly for PAX2 and PAX8, whereas proximal convoluted tubules labeled minimally. The cystic epithelium of all 8 cases of AMLEC, including 5 that protruded beyond the renal capsule into the perirenal fat, demonstrated strong diffuse labeling for both PAX2 and PAX8. We also identified a mimic of entirely extrarenal AMLEC, angiomyolipoma with endosalpingiosis. PAX2 and PAX8 diffusely and strongly labeled the epithelial component of all 8 cases of MEST, including all architectural (phyllodes-like, large cysts, small cysts, clustered microcysts) and virtually all cytologic (hobnail, flat, cuboidal, columnar, apocrine, and clear cell) epithelial variants present. The epithelial cysts of all 3 cases of primary renal SS labeled diffusely and strongly for PAX2 and PAX8. Cyst epithelial labeling intensity was similar to that of renal DCT in all cases. The diffuse labeling for PAX2/PAX8 in the epithelial cysts of AMLEC, taken together with their consistent negativity for estrogen receptor and HMB45, supports the hypothesis that this epithelium represents entrapped, cystically dilated renal tubules that commonly herniate beyond the renal capsule. The diffuse labeling of the cyst epithelium of renal SS supports the previously proposed hypothesis that this cyst epithelium represents entrapped dilated renal tubules in a monophasic spindle cell lesion and not neoplastic epithelial differentiation. The diffuse labeling for PAX2/PAX8 in MEST epithelium, coupled with its usual estrogen receptor negativity, is consistent with the hypothesis that the epithelium of MEST demonstrates renal tubular differentiation and undergoes architectural and cytologic changes as it grows along with the stromal component. Whether this complex epithelium represents entrapped or neoplastic renal tubular epithelium remains an open question.

Clear cell adenocarcinoma of the ovary arising in atypical endometriosis: a report of eight cases

Studies of clear cell adenocarcinoma of the ovary (CCAO) arising from endometriosis are scant. The author reviewed 13 cases CCAO of our pathology laboratory for the presence of endometriosis within the tumor. Eight (61.5%) of the 13 tumors contained endometriosis within the tumor. Of the eight cases, seven were atypical endometriosis and one was ordinary endometriosis. The age of the eight patients with CCAO ranged from 35 to 82years with a median of 52years. Grossly, the ovarian tumors of CCAO were characterized by unilocular cystic lesions containing solitary or multiple nodules in the inner surfaces. The outer surface was smooth and free of tumor. Histologically, the nodules showed typical features of pure CCAO with clear cells, hobnail cells, and hyalinized stroma. The non-nodular flat areas of the tumor were composed of a layer of atypical clear cells and endometriosis consisting of a layer of endometrial epithelium and endometrial stroma. Incipient foci of CCAO were occasionally recognized in the atypical clear cells. Seven cases with endometriosis showed atypia of the endometrial epithelium (atypical endometroiosis), and one case showed no atypia. There was contiguity between the CCAO and atypical clear cells and between atypical clear cells and endometriosis. Contiguity between atypical endometriosis and CCAO was also recognized in a few areas. The outer surface was devoid of tumor cells and endometriosis. The author speculates as follows. An endometrial cyst develops in the ovary. Its epithelium undergoes initiation, thus giving rise to atypical endometriosis consisting of dysplastic or intraepithelial neoplastic epithelium. The atypical endometriosis further undergoes initiation, leading to the atypical clear cells, and ultimately leads to CCAO showing a unilocular cyst consisting of inner masses of CCAO and flat areas composed of a layer of atypical clear cells with incipient CCAO and atypical endometriosis.

腎Tubulocystic carcinomaの1例

A 55-year-old man who presented himself with gross hematuria and right back pain was found to have a right renal mass with evidence of metastasis to the lymph nodes, bone and lung (cT1bN1M1). He underwent a transperitoneal right nephrectomy. Tumor expressed markers of CD10, P504S and CK19 immunohistochemically, so histopathological examination revealed tubulocystic carcinoma of the right kidney (pT3a). After the patient received sunitinib therapy, computed tomography revealed reduction in the size of the metastatic lung nodule and lymph nodes, indicating a partial response. He is alive without disease progression at 12 months after nephrectomy. Tubulocystic carcinoma has been referred to by Amin et al as low-grade collecting duct carcinoma and is not yet included in the World Health Organization (WHO) 2004 classification of renal tumors. The cells lining the tumor range from cuboidal to columnar and have large nuclei with low-grade changes and abundant eosinophilic or amphophilic cytoplasm. Hobnail cells are commonly seen. Immunohistochemically, tubulocystic carcinomas are strongly positive for markers of the proximal nephron (CD10, P504S) and the distal nephron (parvalbumin, CK19). Despite a low nuclear grade, tubulocystic carcinomas occasionally show progressive behavior clinically. Although there is no established salvage therapy, sunitinib was found to be effective for this patient.

Morphologic Spectrum of Immunohistochemically Characterized Clear Cell Carcinoma of the Ovary

Establishing a diagnosis of ovarian clear cell carcinoma (O-CCC) can be subject to significant interobserver variation. Accurately diagnosing this tumor is important because of its chemoresistance and reported association with Lynch syndrome. The spectrum of the morphologic features of O-CCC has not been well described in a series composed of immunohistochemically characterized cases. A total of 155 cases diagnosed as O-CCC were retrieved from the files of 3 institutions to analyze architectural and cytologic features. The immunohistochemical features of these cases have been reported earlier. A comprehensive list of features was recorded, including, but not limited to, architectural patterns, nuclear appearance, cytoplasmic characteristics, and mitotic index. Between 1 and 13 slides were available for review for each case. The cases were divided into 2 groups based on morphologic characteristics, those with features shared by the large majority (the first group, n=138) and those that showed unusual characteristics (second group, n=17). Tumors in the first group typically showed a mixture of architectural patterns, the most frequent being papillary and tubulocystic. Papillae, usually small and round and lacking hierarchical branching and tufting or stratification of more than 3 cells, were present at least focally in almost 3 of 4 cases. The cell shape was predominantly cuboidal, not columnar. Nuclear pleomorphism and prominent nucleoli were frequently present, but never diffusely. Clear cytoplasm was found in nearly every case and hobnail cells were common. Mitoses exhibited a range from 0 to 13 with an average of 3 to 4 per 10 high power fields. The second group of tumors showed numerous unusual morphologic characteristics, despite the presence of clear cytoplasm, including those typically seen in other ovarian epithelial tumors, such as serous and endometrioid carcinoma. Eighty-nine percent of tumors from the first group showed the expected "O-CCC immunophenotype" [hepatocyte nuclear factor (HNF) positive, and estrogen receptor (ER), progesterone receptor (PR), Wilms tumor 1 (WT1) and p53 negative], whereas 4% of tumors showed HNF positivity along with focal ER or PR expression. Seven percent of tumors were not immunoreactive with these markers. Twenty-nine percent of tumors in the second group showed the O-CCC immunophenotype, whereas 24% of tumors were p53 positive, 5% of tumors were WT1 positive, and the remaining cases were negative for all markers. Ninety-seven percent (112 of 117) of HNF-positive tumors in this series were classical O-CCC. Therefore, O-CCC has characteristic morphologic features and a specific, if not unique, immunophenotype in the vast majority of the cases. Clear cell-rich tumors with features that depart from the classical morphologic appearances described herein should suggest the possibility of an alternative diagnosis.

Proteomic screening of completely resected tumors in relation to survival in patients with stage I non-small cell lung cancer

To investigate the early changes in protein function that induce micro-metastasis in early-stage non-small cell lung cancer, we conducted proteomic analysis of tissue that had been completely resected. We selected sixteen patients whose tumors were pathological stage I adenocarcinoma with hobnail cell morphology. We compared their proteomic profiles between patients whose cancers recurred and did not recur after 5 years of follow-up. Proteins extracted from frozen tumor tissue were saturated by CyDye labeling and subjected to two-dimensional difference gel electrophoresis (2D-DIGE). We found approximately 2500 protein spots by DeCyder-DIA software analysis. A random forest classifier to the spot volume data sets revealed 30 extracted spots that were potentially effective marker proteins for distinguishing the recurrence and non-recurrence groups. Among them, Mann-Whitney U-test analysis showed that 15 spots were candidate marker proteins. Finally, 11 unique proteins corresponding to the 15 candidate spots were found using an improved in-gel digestion method and MALDI-TOF MS and nanoLC-ESI MS analysis. Among them, aldehyde dehydrogenase and tropomyosin were considered to have undergone protein modifications such as phosphorylation, acetylation, and glycosylation. We have thus identified some biomarkers that can predict tumor recurrence in patients with early-stage non-small cell lung cancer including hobnail-type adenocarcinoma. A further study is required to confirm the utility of these biomarkers.

Predictive advantage of a cell type classification for pulmonary adenocarcinoma coupled with data for p53, K‐ras and EGFR alterations

We analyzed relationships between histological subtypes of pulmonary adenocarcinomas and three gene alterations (p53, K-ras, and epidermal growth factor receptor gene), or thyroid transcription factor-1 (TTF-1) expression, and also studied prognoses by the subtypes, with or without combined multiple gene mutation status. Our purpose was to clearly determine pathogenesis, along with the best predictive value for biology and therapy-related traits. A total of 223 consecutively resected pulmonary adenocarcinomas were sub-classified using either the World Health Organization (WHO) or our five-cell type (FCT) classification system (hobnail, columnar/cuboidal, mixed, polygonal/oval, and goblet cell types). DNAs extracted from frozen samples of the adenocarcinomas were examined for gene alterations, and TTF-1 expressions were determined using immunohistochemistry. Next, relationships among the various data and clinicopathological factors were analyzed. The most striking result was: while almost 70% of adenocarcinomas were sub-classified as a mixed subtype by WHO, the FCT classified many of them as other cell subtypes. The FCT closely reflected differences in etiological factors, cellular lineages, and frequencies of gene mutations; and whether the data from combined gene mutations were used or not, differences among the cell types in postoperative survivals appeared. In contrast, subtypes of WHO did not show any association with the gene alteration or prognosis, and the FCT more suitably indicated sensitivity to gefitinib therapy than did WHO. The FCT combined with multiple gene mutation status appears to be useful in indicating pathogenesis and predicting the biological nature of pulmonary adenocarcinomas, and it could facilitate development of new therapies for each subtype.

A case of diaphragmatic clear cell carcinoma in a patient with a medical history of ovarian endometriosis

We present a case of clear cell carcinoma located in the diaphragm in a patient with a medical history of ovarian endometriosis. Ultrasonography revealed the presence of a 2.5-cm nodule on the surface of the liver in a 65-year-old woman. She had undergone right salpingo-oophorectomy for treatment of an endometrial cyst of the right ovary at the age of 43years and hysterectomy for treatment of a myoma of the uterus at the age of 51years. We performed laparotomy and found that the tumor had originated from the diaphragm and invaded the liver. The diaphragm and liver were partially resected. Histopathological examination revealed the presence of clear cells and hobnail cells. The clear cells contained pale or eosinophilic cytoplasm and were arranged in a solid pattern. The hobnail cells lined the lumen and papillae. Immunohistochemical examination of the tumor cells showed positive staining for CK-7 and CA-125; negative staining for CK-20, TTF-1, and CA19-9; and weak positive staining for CEA. The findings were compatible with those of ovarian clear cell carcinoma. After 1year, the patient had metastasis in the lung, and right lower lobectomy was performed.

Clear cell adenocarcinoma of the uterine cervix in a young pregnant woman: a case report with immunohistochemical study

The patient was a 30-year-old-pregnant woman (para 1, gradiva 1) without in utero exposure to diethylstilbestrol. A papillary and flat lesion was found by colposcopy in the uterine cervix in the routine examination at 10 pregnancy weeks. Biopsies showed papillary and tubular proliferation of malignant cells with clear glycogen-rich cytoplasm and malignant hobnail cells and were diagnosed as clear cell adenocarcinoma. The patient was treated by radical hysterectomy. The lesion of the cervix (10 × 15 × 5 mm) was clear cell adenocarcinoma with mild invasion into shallow myometrium (pTIb). An immunohistochemical study showed that the tumor cells were positive for pancytokeratins (AE1/3, CAM5.2, KL-1, and polyclonal wide), cytokeratin (CK) 7, CK8, CK18, CK19, epithelial membrane antigen, CA 125, p53 protein, and Ki-67 antigen (labeling = 95%). The tumor cells were negative for high-molecular weight CK (34βE12), CK5/6, CK14, CK20, vimentin, AFP, CEA, desmin, S100 protein, α-smooth muscle antigen, CD34, estrogen receptor, progesterone receptor, chromogranin, synaptophysin, neuron-specific enolase, and CD56. The patient is now of free of tumor. In the English literature, the present case is the second case of cervical clear cell adenocarcinoma during pregnancy, and the first case of cervical clear cell carcinoma investigating a wide range of immunoreactive antigens.

Is the Epidermal Growth Factor Receptor Status in Lung Cancers Reflected in Clinicopathologic Features?

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are molecular-targeted drugs that are innovatively effective for non-small cell lung carcinomas with EGFR mutations. Epidermal growth factor receptor is a transmembrane receptor forming dimers on ligand binding. These then stimulate signals by activating receptor autophosphorylation through tyrosine kinase activity. Autophosphorylation triggers intracellular pathways facilitating malignant conversion. The most clinically advanced EGFR inhibition strategies include small-molecule inhibition of the intracellular tyrosine kinase domain (gefitinib and erlotinib) and monoclonal antibody-mediated blockade of the extracellular ligand-binding domain (cetuximab). Lung cancers with EGFR mutations are prevalent among patients who are female, of Asian ethnicity, and nonsmokers; thus, they can obtain benefit from EGFR tyrosine kinase inhibitors. To survey histopathologic findings and examine correlations with EGFR mutations. We mainly focused on component cell types (hobnail, columnar, and polygonal) and presence or absence of bronchioloalveolar carcinoma elements and a micropapillary pattern. Although EGFR mutations can be detected by various methods, including polymerase chain reaction-Invader assay or direct sequencing, these are inconvenient. Review of the published literature. Detailed pathologic examination showed significant genotype-phenotype correlations between EGFR mutations and presence of a bronchioloalveolar carcinoma component, a micropapillary pattern, and the hobnail cell type. We conclude that these characteristic histologic features are good predictors of EGFR mutations, and patients with these features might be good candidates for and could benefit from therapy with EGFR tyrosine kinase inhibitors.

Tubulocystic Carcinoma of the Kidney

A distinctive tumor described under the terms Bellini duct carcinoma and low-grade collecting duct carcinoma has been referred to by us and others as tubulocystic carcinoma. This renal cell carcinoma subtype is not recognized in the World Health Organization 2004 classification. Herein, we present a detailed study of 31 cases to further characterize this rare subtype of renal cell carcinoma. The tumor occurred in adults (mean age, 54 years) with a strong male predominance (7:1). Grossly, the tumors ranged from 0.7 to 17 cm, and exhibited a spongy or "bubble wrap" appearance reflecting the microscopic presence of variably sized cystically dilated tubules lined by a single layer of epithelium. The lining varied with a cuboidal, flat, and hobnail cell appearance, and the neoplastic cells had abundant eosinophilic cytoplasm and enlarged nuclei with prominent nucleoli. The cysts were closely spaced with an intervening variably fibrotic stroma. Immunohistochemistry and ultrastructural examination showed features of proximal convoluted tubules (Pax 2 immunoreactivity and short microvilli with brush border organization) and distal nephron (kidney-specific cadherin immunoreactivity and cytoplasmic interdigitation). Gene expression profiling showed that tubulocystic carcinoma displayed a unique molecular signature. Twenty-four tumors were stage pT1, 4 stage pT2, and 3 stage pT3. Disease progression (median follow-up of 56 months) occurred in 3 patients; 1 with local recurrence, and 2 with distant metastasis to bone and liver. In light of the distinctive clinicopathologic features and a low but definite metastatic potential, this unique subtype of renal cell carcinoma deserves formal recognition in the contemporary classification of renal neoplasms.