C4d immunohistochemical staining is a sensitive method to confirm immunoreactant deposition in formalin-fixed paraffin-embedded tissue in membranous glomerulonephritis.

Although the diagnosis of membranous glomerulonephritis (MGN) may be suspected on routine histology of formalin-fixed paraffin-embedded tissue, fresh-frozen tissue must be used to show the immunologic nature of the process by direct immunofluorescence (IF). The efficiency of IF or immunoperoxidase (IP) detection of IgG and C3 using paraffin sections is controversial. This study was designed to evaluate whether glomerular C4d deposition using an IP method in formalin-fixed paraffin-embedded tissue may be a useful marker for MGN. We showed characteristic glomerular, granular basement membrane deposition of C4d in 31 (100%) cases of idiopathic MGN and in 5 cases (100%) of pure class V membranous lupus nephritis, in which we had a positive diagnosis of the lesions for conventional IF study. Control cases were negative. Nineteen cases of different glomerulopathies, including IgA nephropathy, primary type I membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis and minimal change disease showed diverse reproducible patterns of C4d deposition, without intrinsic background. Our results indicate that staining of formalin-fixed paraffin-embedded tissue for C4d can be used for confirmation of granular basement membrane immunoreactant deposition in cases of MGN. This proved to be a reliable method that could potentially obviate the need for rebiopsy in cases with absence of glomeruli in renal frozen sections or when other adjunct IF or IP methods on paraffin sections are negative. C4d immunostaining, using an IP method, deserves a place as an adjunct method in the biopsy diagnosis of MGN.

An overview of the pale and clear cells of the nipple epidermis.

The stratified squamous epithelium of the nipple-areola complex may contain pale or clear cells including: Paget's disease cells (PDCs), Toker cells (TCs), and so-called clear cells (CCs). Paget's disease is an uncommon presentation of breast carcinoma. PDCs are large, atypical, have abundant, pale-staining cytoplasm that may contain mucin secretion vacuoles and bulky heterochromatic nuclei. They are commonly concentrated along the basal layer and stain for EMA, CAM5.2, cytokeratin 7, and HER2/neu oncoprotein. TCs are bland cells with roundish and scant chromatin nuclei. They are found incidentally and are reactive for EMA, CAM5.2, and cytokeratin 7, but show negativity for HER2/neu oncoprotein. So-called CCs show varied morphology, are found incidentally, and have been variably interpreted by different authors. The majority of cells that have been called epidermal CCs fit the features of pagetoid dyskeratosis. These cells are reactive for high molecular weight cytokeratin. Other CCs showing signet-ring morphology present negativity for mucins and correspond to a fixation artefact.

Concurrent tubulovillous adenoma and transitional cell carcinoma associated with diffuse gastric and intestinal metaplasia of the defunctioned ureter.

Villous adenoma is a common lesion of the gastrointestinal tract, but it is rare in the ureter. Thus, as far as we know, only one case limited to this location has been described. Intestinal metaplasia of the urothelium is not rare. However, only one case of gastric metaplasia with pseudopyloric glands has been described in the literature. We here report in detail on a tubulovillous adenoma of the ureter associated with diffuse gastric and intestinal metaplasia and a concurrent primary, solid, high grade transitional cell carcinoma, with extensive clear cell change, in a 56-year-old male patient. He had undergone a left nephrectomy for renal tuberculosis twenty years earlier, and the lesions developed in the ureteric stump. To the best of our knowledge, such a combination of lesions has not been reported previously either in the ureter or in the rest of the urinary tract. The coexistence of diverse lesions in our case might represent the pluripotentiality of the urothelium in association with chronic inflammation and neoplastic induction. The present report also emphasizes the metaplastic and malignant potential of a defunctioned urothelial structure. This case is of particular interest, because these coexistent lesions arose simultaneously with an anatomically separate adenocarcinoma of the rectum (Dukes' B). The patient died 76 days after admission. The dismal prognosis of our case was determined by the advanced anatomical stage and the histological high grade of the transitional cell carcinoma of the ureter.

Pagetoid dyskeratosis of the lips.

Pagetoid dyskeratosis is an incidental finding in a variety of lesions of the skin and squamous mucosa. The lesion is considered a selective keratinocytic response in which a small part of the normal population of keratinocytes is induced to proliferate in response to friction. As far as we know, pagetoid dyskeratosis has not been reported in the lips. In this article, we describe the location of the lesion in the lips and its incidence in a group of 90 unselected patients who underwent biopsy or were surgically treated for diverse labial lesions. Histochemical staining and immunohistochemical studies were performed in selected cases. Pagetoid dyskeratosis was found in 38 cases (42.2%) but only in 6 cases (6.7%) the lesion was conspicuous. There was no significant difference between the upper and the lower lip in terms of incidence of the lesion. Labial pagetoid dyskeratosis was more frequent in younger patients (46.7 +/- 25.0 versus 58.5 +/- 20.5; p < 0.05) and in women (chi(2) = 3.89; p < 0.05). Pagetoid cells were more common in suprabasal location and in the labial mucosa. These cells showed positivity for high-molecular weight cytokeratin and negative reaction for low-molecular weight cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, and human papilloma virus. The immunohistochemical profile is different from the surrounding keratinocytes, indicating premature keratinization. The main differential diagnoses include white sponge nevus, leukoedema, oral koilocytoses, hairy leukoplakia, pagetoid squamous cell carcinoma in situ, and extramammary Paget's disease of the oral mucosa. The morphologic features of dyskeratotic pagetoid cells are distinctive and easily recognized as an incidental finding, thus preventing confusion with other important entities including an intraepidermal tumor.

MIB1 proliferation index in breast infiltrating carcinoma: comparison with other proliferative markers and association with new biological prognostic factors.

AIMS: In breast invasive carcinoma our objectives were I) to compare cellular proliferation determined by MIB1 index with S-phase fraction (SPF) assessed by flow cytometry and with mitotic index, and II) to examine the association of MIB1 index with classical and with new biological prognostic factors [bcl-2, p53, c-erbB-2 and cathepsin D (CD)]. METHODS AND RESULTS: From 102 cases of breast invasive carcinoma, 5-microm thick serial sections were cut from formalin-fixed, paraffin-embedded tissue blocks, and processed for detection of CD, c-erbB-2, p53, bcl-2, Ki-67 antigen MIB-1 and estrogen receptors (ER) and progesterone receptors (PR). SPF was measured by flow cytometry in fresh-frozen tissue samples taken from the carcinoma in each patient. MIB1 index was correlated with SPF (rho=0.45, p<0.0001) and with mitotic index (rho=0.42, p<0.0001). The MIB-1 index was positively associated with the histological grade (p=0.001), tumor size (p=0.04) and the presence of metastases in axillary lymph nodes (p=0.01). MIB1 was associated directly with p53 (p=0.045) and inversely with bcl-2 (p=0.0002). The MIB-1 index was not statistically associated with c-erbB-2. There was a weak association between MIBI index and stromal cell CD. The median MIB1 index was higher in tumors with moderate to strong CD staining of stromal cell, but the difference did not reach statistical significance (p=0.09). CONCLUSIONS: MIB1 index correlates with well established methods for assessing tumor proliferation and with parameters of an aggressive phenotype of tumor. MIB1 index is an effective and readily accessible method for assessing tumor proliferation in breast carcinoma.

Pagetoid dyskeratosis of the cervix: an incidental histologic finding in uterine prolapse.

Pagetoid dyskeratosis, is considered a reactive process in which a small part of the normal population of keratinocytes is induced to proliferate. The lesion is characterized by pale cells resembling those of Paget's disease within the epidermis. These cells have been seen as an incidental finding in a variety of benign papules most commonly located in intertriginous areas. Among the inductors of the lesion, friction is suspected. To the best of our knowledge, these pale cells have not been reported in the cervix. We describe the location of the lesion in the ectocervix and the incidence of this lesion in a group of 100 unselected patients surgically treated for uterine prolapse. Another group of 100 unselected patients treated for uterine leiomyoma was used as a control. Pagetoid dyskeratosis was found in 37 cases (37%) of uterine prolapse and in five cases (5%) of uterine leiomyomas. The lesion is more common in uterine prolapse (p <0.001) and is not significantly associated with cornification of the epithelium (p = 0.72343). The cells of pagetoid dyskeratosis show an immunohistochemical profile different from the surrounding squamous cells characterized by premature keratinization. Pagetoid dyskeratosis cells have shown positivity for high molecular weight cytokeratin and negative reaction for low molecular weight cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, and human papilloma virus. Pagetoid dyskeratosis cells must be distinguished from artefactual clear cells, glycogen-rich cells, koilocytes, extramammary Paget's disease cells, and pagetoid spread of carcinoma cells to the cervix. In cases in which pagetoid dyskeratosis shows a florid expression, there is a hazard of overdiagnosis. The pathologist should be aware of the histologic features of pagetoid dyskeratosis in the ectocervix to avoid misdiagnosis and unnecessary treatment. Routine histologic study is usually sufficient to identify the lesion.

Association of cystic nephroma with angiomyolipoma in the same kidney.

The synchronous occurrence of two different renal tumors in a patient is a rare event. Here we report an incidentally discovered coexistence of cystic nephroma with angiomyolipoma in the right kidney. The patient was a 68-year-old woman without the tuberous sclerosis complex. To the best of our knowledge, this combination of neoplasms has not yet been described before. This rare situation emphasizes the need for careful diagnosis and the correct management of coincident renal neoplasms.

Pagetoid dyskeratosis of the prepuce. An incidental histologic finding resembling extramammary Paget's disease.

BACKGROUND: Pale cells resembling those of paget's disease have been seen as an incidental finding within the epidermis in a variety of benign papules most commonly located in intertriginous areas. This lesion, called pagetoid dyskeratosis, is considered a reactive process in which a small part of the normal population of keratinocytes is induced to proliferate. Among the inductors friction is suspected. As far as we know, these cells have not been reported in the penis. METHODS: Here we describe the location of the lesion in the foreskin and the incidence of this lesion in a group of 281 unselected patients surgically treated for phimosis. In selected cases histochemical staining and immunohistochemical studies were performed. RESULTS: Pagetoid dyskeratosis was found in 105 cases (37.4%) but only in 5 cases (1.8%) the lesion was conspicuous. The cells of pagetoid dyskeratosis show an immunohistochemical profile different from the surrounding keratinocytes characterized by premature keratinization. Pagetoid dyskeratosis cells must be distinguished from the artefactual clear cells of the epidermis, from reactive melanocytes, and from pale-cell acanthosis. In cases in which pagetoid dyskeratosis shows a florid expression there is a hazard of overdiagnosis to the patient. The main differential diagnosis includes extramammary Paget's disease, pagetoid squamous cell carcinoma in situ, epidermotropic metastasis, superficial spreading malignant melanoma, clear cell papulosis, and penile koilocytoses. CONCLUSIONS: The pathologist should be familiar with the histologic features of pagetoid dyskeratosis in the foreskin in order to avoid misdiagnosis and unnecessary treatment. Routine histologic study is usually sufficient to identify the lesion.

Predictors of axillary lymph node metastases in patients with invasive breast carcinoma by a combination of classical and biological prognostic factors.

The presence of axillary lymph node metastases (ALNMs) is the most important prognostic factor in breast carcinoma. If ALNMs were predictable without performing axillary lymph node dissection (ALND), this procedure would not be necessary in selected patients. Using a combination of some of the new biological markers with the classical ones, our objective was I) to identify the best set of predictors of ALNMs, and II) to define predictive models with either high or low probability of ALNMs. We studied 102 patients with invasive breast carcinoma. All patients underwent ALND, and at least 10 axillary lymph nodes per case were obtained. In the primary tumour we evaluated size, histological subtype and grade, lymphatic/vascular invasion and margin. Hormone receptor status, MIB1 index, microvessel density, c-erbB-2 and cathepsin D expression were assessed by immunohistochemistry, and DNA ploidy and S-phase by flow cytometry. Risk factors for ALNMs were estimated by nonlinear logistic regression analysis. The best predictors of ALNMs were: tumour size > 2 cm [OR 6.45, 95% confidence interval (CI) 21.74 to 1.91], presence of lymphatic/vascular invasion [OR 4.95, CI (14.50 to 1.69)], infiltrative margin [OR 9.87 CI (37.44 to 2.60)] and high MIB-1 index [OR 8.39, CI (33.47 to 2.10)]. Two subsets had a very high risk of ALNMs: I) tumour size > 2 cm, with lymphatic/vascular invasion and infiltrative margin; 26 (89.66%) of 29 patients of this subgroup had ALNMs, and (II) tumour size > 2 cm, with lymphatic/vascular and high MIB1 index.; eight of the nine (89%) patients of this subgroup had ALNMs. We could also identify a two-variable model with a very low risk of ALNMs constituted by tumour with circumscribed margin and low MIB-1 index. Of the 19 patients showing these features, only 1 (5.26%) had ALNMs. Therefore, pathological features of the primary tumour can help to assess the risk for ALNM in invasive breast carcinoma. Such risk assessment might avoid regional surgical overtreatment.

Pilonidal sinus of the penis. A report of two cases, one of them associated with actinomycosis.

Pilonidal sinus is a long-standing chronic inflammatory condition which occurs most commonly in the sacrococcygeal area and it is rare in the penis. Two cases of penile pilonidal sinus in patients aged 25 and 28 years are reported and the literature is reviewed. The lesion is acquired and has to be distinguished from balanoposthitis, epidermal cyst and carcinoma. For pilonidal sinus to occur at this site, it is hypothesized that the coronal sulcus acts as a cleft where hair may accumulate and be driven into the shaft and prepuce by the natural movement between these two surfaces. One of our cases was associated with actinomycosis. Actinomycosis associated with pilonidal sinus of the penis is extremely rare and there are only two previous reports. It is suggested that pilonidal sinus may have been predisposed to the infection with the actinomyces organisms. Information stating that penile pilonidal sinus and actinomycosis may occur simultaneously is necessary to accomplish an early diagnosis.

Cathepsin D in host stromal cells is associated with more highly vascular and aggressive invasive breast carcinoma.

AIMS: To determinate the relationship between tumoral angiogenesis and cathepsin D (CD) expression in tumour and host stromal cells of invasive breast carcinoma, and to examine its association with classical prognostic factors such as lymph node status, histological grade, tumour size, mitotic rate, peritumoral lymphovascular invasion and oestrogen receptor (ER) status. METHODS AND RESULTS: Sections from 102 invasive breast carcinoma were cut from the archival formalin-fixed, paraffin-embedded tissue blocks and stained using immunohistochemistry for the endothelial cell adhesion molecule (CD31) and CD. Microvessel density was assessed by counting vessels in the three most vascular areas at x400 field. The counts were expressed as the highest counts within any x400 field. The evaluation of immunostaining for CD was performed separately in both the parenchymal and stromal cells. Microvessel density was correlated positively with histological grade and peritumoral lymphovascular invasion, and correlated inversely with ER status. Positive CD staining of tumour cells was more frequent in positive ER tumours and was not significantly associated with the other classical prognostic factors. However, moderate to strong staining of host cells was correlated with higher histological grade, higher mitotic index and lack of ER protein. There was a statistically significant association between CD expression of host stromal cells and higher vessel count. CONCLUSIONS: CD in host stromal cells is associated with more aggressive tumours and with a higher intratumoral microvessel density. Evaluation of CD in combination with angiogenic activity may be of some help in more accurately predicting the biological behaviour of breast carcinoma.

Amyloidosis of the rectum mimicking collagenous colitis.

Gastrointestinal involvement in cases of systemic amyloidosis is very common. In the colorectal mucosa, amyloid deposition is ordinarily seen around vessels or diffusely in the lamina propria. We report two cases in men aged 69 and 29 years, whose rectal biopsies revealed prominent subepithelial amyloid deposits mimicking collagenous colitis. The amyloid deposits were composed of AA protein. A review of the literature has yielded only one previously reported case. Pathologists should be aware of this deposition pattern of amyloid to prevent misdiagnosis. Our cases underline the importance of the routine use of histochemical stains for amyloid in all cases of colorectal biopsies showing histologic changes suggestive of collagenous colitis.

Extravulvar subcutaneous cellular angiofibroma.

Cellular angiofibroma is a rare distinctive mesenchymal neoplasm of the vulva or perineal region. We report here one unique extravulvar case. A 43-year-old woman presented with an asymptomatic tumor, 7 cm in diameter, located in the subcutaneous tissue of the chest below the left submammary sulcus. Histologically, the lesion was composed of uniform spindled stroma cells, numerous thick-walled vessels, and scarce mature adipocytes. An additional feature was the presence of prominent perivascular lymphoid aggregates. The stromal cells were positive for vimentin and negative for CD34 and muscle, epithelial, myoepithelial, or neural markers. Although nasopharyngeal angiofibroma or the group of acral angiofibromas have a concurrent heading, cellular angiofibroma should not be mistaken with them. Differential diagnosis of this distinctive tumor especially includes aggressive angiomyxoma, angiomyofibroblastoma, superficial angiomyxoma, vascular myxolipoma, and other tumors with spindle cells reminiscent of those in angiofibroma.

Renal perineurioma in childhood.

Perineurioma of the kidney in a 7-year-old girl is described. The tumor in the upper pole was discovered during the evaluation of a urinary tract infection. The neoplasm measured 2.6 cm and radiographically it mimicked a nephroblastoma. The diagnosis of perineurioma was confirmed with histologic, immunohistochemical, and ultrastructural studies. These revealed findings typical of perineurioma of other locations. Histopathologically, differential diagnosis may include nephroblastoma, mesoblastic nephroma, neurofibroma, schwannoma, malignant peripheral nerve sheath tumor with perineural cell differentiation, and other benign and malignant mesenchymal tumors with spindle cell pattern. To the best of our knowledge, we report a unique renal perineurioma in a child.

Mammary hamartoma with brown adipose tissue.

This report documents a rare variant of mammary hamartoma with presence of lobules of brown adipose tissue. The lesion was discovered in a control mammogram performed in a 42-year-old woman 15 months after hormonal substitute therapy for radical hysterectomy with bilateral salpingo-oophorectomy. Complete excision is the adequate therapy. The presence of brown fat in the hamartoma should be considered in the differential diagnosis of the exceptional hibernoma of the breast and other tumors composed of large cells with granular or multilocular cytoplasm, such as lipoblastoma, sebaceous adenoma, granular cell tumor and histiocytoid or lipid rich carcinomas.

Primary acute torsion of the vermiform appendix.

A case of primary acute appendiceal torsion in a 6-year-old boy with symptoms suggestive of acute appendicitis is presented. The appendix was abnormally long, measuring 13.5 cm in length. Although appendicitis is the most common intra-abdominal surgical emergency, there are few descriptions of primary acute appendiceal torsion, a rare cause of an acute abdomen. A review of the English language literature disclosed 19 reports, including the present, with 11 pediatric cases. The site of torsion occurs most frequently 1 cm or more from the appendiceal base. Rotation varies from 270 degrees to 1080 degrees with a mean of 580 degrees. The direction of the rotation is more frequently anticlockwise. Appendix is most commonly described as lying free or pelvic. In children the mean age is 9.1 years, the range 3-16 years, and the male-to-female ratio 4.5:1.