Prostate adenocarcinomas aberrantly expressing p63 are molecularly distinct from usual-type prostatic adenocarcinomas.

We have described a rare group of prostate adenocarcinomas that show aberrant expression of p63, a protein strongly expressed in prostatic basal cells and absent from usual-type acinar prostate cancers. The partial basal-like immunophenotype of these tumors is intriguing in light of the persistent debate surrounding the cell-of-origin for prostate cancer; however, their molecular phenotype is unknown. We collected 37 of these tumors on radical prostatectomy and biopsy and assessed subsets for a diverse panel of molecular markers. The majority of p63-expressing tumors were positive for the ΔNp63 isoform (6/7) by immunofluorescence and p63 mRNA (7/8) by chromogenic in situ hybridization. Despite p63 positivity, these tumors uniformly expressed luminal-type cytokeratin proteins such as CK18 (13/13), CK8 (8/8), and markers of androgen axis signaling commonly seen in luminal cells, including androgen receptor (10/11), NKX3.1 (8/8), and prostein (12/13). Conversely, basal cytokeratins such as CK14 and CK15 were negative in all cases (0/8) and CK5/6 was weakly and focally positive in 36% (4/11) of cases. Pluripotency markers including ß-catenin, Oct4, and c-kit were negative in p63-expressing tumors (0/11). Despite nearly universal expression of androgen receptor and downstream androgen signaling targets, p63-expressing tumors lacked ERG rearrangements by fluorescence in situ hybridization (0/14) and ERG protein expression (0/37). No tumors expressed SPINK1 or showed PTEN protein loss (0/19). Surprisingly, 74% (14/19) of p63-expressing tumors expressed GSTP1 protein at least focally, and 33% (2/6) entirely lacked GSTP1 CpG island hypermethylation by bisulfite sequencing. In contrast to usual prostatic adenocarcinomas, prostate tumors with p63 expression show a mixed luminal/basal immunophenotype, uniformly lack ERG gene rearrangement, and frequently express GSTP1. These data strongly suggest that p63-expressing prostate tumors represent a molecularly distinct subclass and further study of this rare tumor type may yield important insights into the role of p63 in prostatic biology and the prostate cancer cell-of-origin.

Prostatic stromal neoplasms: differential diagnosis of cystic and solid prostatic and periprostatic masses.

OBJECTIVE: The objectives of this article are to illustrate the radiologic-pathologic correlation of prostate stromal neoplasms and to review the imaging appearances of cystic and solid prostatic and periprostatic masses that may mimic prostatic stromal neoplasms. CONCLUSION: The differential diagnosis for cystic and solid masses in the prostate is broad, and masses arising from periprostatic structures may mimic the appearance of primary prostatic diseases. Attention to clinical and imaging features is helpful in narrowing the differential diagnosis.

Fibrolamellar carcinomas are positive for CD68.

Fibrolamellar carcinomas are a unique type of liver carcinoma that arise in non-cirrhotic livers of young individuals. Despite their distinctive appearance, recent studies have demonstrated a lack of consistency in how fibrolamellar carcinomas are diagnosed by pathologists. As a potential aide in diagnosis, we investigated the staining properties of CD68. The CD68 gene encodes for a transmembrane glycoprotein located within lysosomes and endosomes. Macrophages as well as other cell types rich in lysosomes/endosomes are CD68 positive. Cases of fibrolamellar carcinoma were collected from four academic centers. Control groups included hepatocellular carcinomas arising in both non-cirrhotic livers and cirrhotic livers. A group of cholangiocarcinomas were also stained. CD68 immunostaining was scored for both intensity and distribution on a scale of 0 to 3+. Twenty-three primary fibrolamellar carcinomas and 9 metastases (total of 24 individuals) were immunostained and showed a distinctive granular, dot-like or stippled pattern of cytoplasmic staining in nearly all cases (31/32), with a median distribution and intensity score of 3+. In control hepatocellular carcinomas that arose in non-cirrhotic livers, 10/39 showed CD68 staining with a median distribution and intensity score of 2+. In hepatocellular carcinomas arising in cirrhotic livers, 3/27 cases showed CD68 positivity, all with stippled dot-like cytoplasmic staining similar to that of fibrolamellar carcinomas. All five cholangiocarcinomas were negative. Overall, CD68 positivity was strongly associated with fibrolamellar carcinomas, P<0.001 and had a sensitivity of 96%, a specificity of 80%, and a negative predictive value of 98%. In sum, tumor positivity for CD68 staining was highly sensitive for fibrolamellar carcinoma and a lack of CD68 staining should suggest caution in making a diagnosis of fibrolamellar carcinoma.

ΔNp63 (p40) expression in prostatic adenocarcinoma with diffuse p63 positivity.

Basal cells of benign prostate glands are typically p63 positive, whereas malignant glands are usually p63 negative. A rare subset of prostatic adenocarcinoma (PCa) demonstrates aberrant diffuse p63 expression but is negative for high-molecular-weight cytokeratin. Strong p63 staining of the tumor cells can obscure the loss of high-molecular-weight cytokeratin when using a cocktail of basal cell markers and create a diagnostic pitfall. The p63 protein has 6 major isoforms; of these, TAp63 and ΔNp63 (p40) are the best characterized N-terminal variants. In an attempt to aid in the diagnosis of p63-positive PCas, we studied ΔNp63 expression in tumors with aberrant p63. Immunohistochemistry was performed on 31 cores of aberrant p63-positive PCas from 24 patients and on a tissue microarray containing 125 cores of conventional PCas from 40 radical prostatectomy cases using a ΔNp63-specific polyclonal (p40) antibody and a TAp63-specific monoclonal antibody (p63, clone 4A4) that recognizes both TAp63 and ΔNp63. Most of the aberrant p63-positive tumors showed diffuse positivity for p40 (29/31 cores, 93.5%; 23/24 cases, 96%). All 40 conventional PCa (125 cores) were negative for p40 and p63 in the tumor cells. In summary, p40 is expressed in most p63-positive PCas but negative in p63-negative conventional PCas. From a diagnostic perspective, the use of immunohistochemistry for ΔNp63/p40 provides only a small advantage over the more widely used p63 assays. Our 1 ΔNp63-negative p63-positive case may represent expression of the TAp63 isoform in the tumor.

Squamous neoplasia of the scrotum: a series of 29 cases.

The current epidemiology and clinicopathologic features of squamous cell carcinoma (SCC) of the scrotum are largely unknown because of its low incidence. We describe the histopathologic features, immunohistochemistry, and human papillomavirus (HPV) status of 29 patients with scrotal SCC. The mean age at presentation was 55 years (range, 30 to 74 y). White to black ratio was 1.9:1. There was no predominant occupation, with the majority being white-collar professionals. Clinical history of condylomas was present in 5 patients, and 7 patients had a history of multiple skin cancers including melanoma, basal cell carcinoma, and other SCCs. Other comorbidities included human immunodeficiency virus infection (n=2), kidney transplant (n=1), leukemia/lymphoma (n=2), hidradenitis suppurativa (n=1), chronic scrotal infections with abscess (n=1), inflamed epidermal inclusion cyst (n=1), and lichen planus (n=1). One patient had a history of regular tanning bed use. Morphologically, the majority was usual type (n=17), followed by basaloid (n=7) and warty (n=5). Nineteen cases were in situ, and 10 were invasive. Three patients had inguinal lymphadenopathy; in 1, metastasis was confirmed. Suprabasal nuclear staining for Ki67 was considered positive. For p16, a continuous band of nuclear and cytoplasmic staining was considered positive, and a noncontinuous or absence of staining was considered negative. p16 was positive in 10 cases; high-risk HPV was confirmed in 7 cases. Ki67 was positive in 8/17 (47%) usual, 6/7 (85.7%) basaloid, and 3/5 (60%) warty type. p53 was positive in 5/17 (29.4%) usual, 2/7 (28.6%) basaloid, and 1/5 (20%) warty type. All patients were treated with local excision only; 13 had positive margins. Three patients were treated with imiquimod after local excision. The median follow-up was 30 months. Three patients recurred and were treated with re-excision; 1 patient received radiotherapy. Overall, the morphologic, immunohistochemical, and HPV studies show that, similar to SCC of the vulva or penis, the SCC of the scrotum can be divided into 2 major groups. Group 1 (38.5%): positive for p16 and elevated Ki67. This group is associated with HPV infection and displays predominantly a basaloid or warty morphology, although a number of them are of usual type. Group 2 (61.5%): negative for p16. This group has variable Ki67 expression, is consistently negative for HPV, and displays predominantly usual-type morphology. SCC of the scrotum in the United States currently affects primarily white-collar professionals. The majority present with in situ lesions, and the high rate of positive margins at first excision suggests that they are clinically ill-defined lesions. No longer are occupational exposures to carcinogens the major etiology of scrotal SCC. Rather in contemporary times, common risk factors include HPV infection, immunocompromised states, and chronic scrotal inflammatory conditions.

Nephrogenic adenoma: a report of 3 unusual cases infiltrating into perinephric adipose tissue.

Nephrogenic adenoma of the urinary bladder, where they present most frequently, are typically confined to the lamina propria but can on occasion focally involve the superficial muscularis propria. Less commonly, nephrogenic adenoma involves the renal pelvis and ureter where again they almost always only involve the lamina propria. We identified 3 consult cases in which tubules of nephrogenic adenoma extensively involved the muscularis propria and focally infiltrated the perinephric adipose tissue, for which the contributing pathologists considered the diagnosis of adenocarcinoma. In 1 case, that of a 71-year-old man, the lesion was associated with a hemorrhagic renal cyst (3.0 cm) and a spontaneous retroperitoneal bleed (6.0 cm) of unknown origin. In the second case, that of a 73-year-old woman, 2 foci (2.2, 1.6 cm) were present in the renal pelvis. They developed after biopsy of a low-grade noninvasive papillary urothelial carcinoma in the same site complicated by perforation. The third case was that of a 20-year-old woman with ureteropelvic junction obstruction and severe hydronephrosis associated with renal calculi. In all cases, the lesions were positive for CK7 and PAX8. These 3 cases report the novel finding that nephrogenic adenoma can occasionally have a deep infiltrative pattern into perinephric adipose tissue, possibly as a result of either biopsy-associated perforation or extensive disruption due to hemorrhage or mechanical obstruction. Awareness of this worrisome infiltration pattern, although rare, can prevent a misdiagnosis of an infiltrating carcinoma.

Aberrant expression of p63 in adenocarcinoma of the prostate: a radical prostatectomy study.

Prostatic adenocarcinoma with aberrant diffuse expression of p63 (p63-PCa) is a recently described variant of prostatic adenocarcinoma. The aim of this study was to investigate the clinical and pathologic features of p63-PCa at radical prostatectomy (RP). We reviewed 21 cases of p63-PCa diagnosed on needle biopsy at subsequent RP. Immunohistochemical analysis for PIN4 and Ki-67 was performed in all RP cases. p63-PCa showed a distinctive morphology consisting of atrophic, poorly formed glands, with multilayered and often spindled nuclei. Gleason grading was 3+3=6 in 28.5%, 3+5=8 in 38%, 3+4=7 in 14.3%, and 4+3=7, 5+3=8, and 5+4=9 in 9.5%. Usual-type acinar carcinoma coexisted in 85.7% with only p63-PCa present in the remaining cases. The usual-type carcinoma was Gleason grade 3+2=5 in 4.7%, 3+3=6 in 57%, 3+4=7 in 19%, and 4+3=7 in 4.3%. Overall, p63-PCa represented 65% of the total cancer volume (median 80%). The tumor was organ-confined in 16 cases (76.2%). In the remaining 5 cases, 2 had p63-PCa extending to the margin in areas of intraprostatic incisions, 2 had usual-type acinar adenocarcinoma extending to the margin and extraprostatic tissue, respectively, and 1 had p63-PCa with an unusual cribriform morphology involving the bladder neck. Ki-67 was low, <5% in all cases of p63-PCa, with similar expression in the coexisting acinar-type carcinoma. In summary, it is recommended that these tumors not be assigned a Gleason score and their favorable findings at RP be noted.

Massive localized lymphedema of the male external genitalia: a clinicopathologic study of 6 cases.

Massive localized lymphedema is a reactive pseudotumor strongly associated with obesity. The tumor most commonly presents as pendulous masses in the lower limbs with only 3 reported cases involving external male genitalia. In this study, we report an additional 6 cases localized to the external male genitalia. The cases were retrospectively identified from the surgical pathology database of the Johns Hopkins Hospital. All 6 patients were obese (5 presented with diffuse scrotal edema and 1 with a penile mass). In all cases, the clinical impression was of a benign chronic process developing over 3 months to 1 year. All 3 cases from outside institutions were referred with benign pathologic diagnoses. The lesions ranged in size from 4 to 55 cm. Microscopically, all cases exhibited stromal fibrosis and edema, multinucleated stromal cells, perivascular chronic inflammation, and lymphangiectasia. Entrapped fat was a minor feature and seen in only 3 cases. Variable hyperplasia and hypertrophy of dartos muscle were noted in 6 lesions. Three cases showed prominent microvascular proliferation around the edge of individual dartos muscle bundles. In summary, diagnosis of massive localized lymphedema requires appropriate correlation between clinical and microscopic findings. Lesions in the male external genitalia share many microscopic findings with massive localized lymphedema at other sites, although entrapped adipose tissue is not prominent. Additional, although not specific, findings include variably hyperplastic and hypertrophic dartos muscle and capillary neoangiogenesis at the interface between smooth muscle bundles and stroma.

Small cell-like change in prostatic intraepithelial neoplasia, intraductal carcinoma, and invasive prostatic carcinoma: a study of 7 cases.

Small cell carcinoma of the prostate is associated with poor prognosis and different treatment from conventional acinar adenocarcinoma. Given the important clinicopathologic implications of a diagnosis of small cell carcinoma, we report 7 cases showing unusual, extensive small cell-like change in intraductal carcinoma and invasive carcinoma. Prostatic biopsies from 3 patients and radical prostatectomy specimens from 4 patients showed variably extensive small cell-like high-grade prostatic intraepithelial neoplasia and intraductal carcinoma. Five cases were associated with conventional acinar adenocarcinoma (2 cases with Gleason score 4 + 3 = 7; 3 cases with Gleason 3 + 4 = 7). No small cell carcinoma was seen. Small and large ducts with small cell-like change showed solid and cribriform proliferations of atypical cells with abrupt transition between centrally located populations of small cells and more typical large dysplastic cells at the duct periphery. Rosette-like formations were noted within some involved ducts. Small cell-like change was characterized by crowded cells with uniformly bland vesicular nuclei and minimal cytoplasm and no significant mitotic or apoptotic activity. In 3 cases, similar small cell-like morphology was noted focally in invasive carcinoma. The small cell-like areas were negative for synaptophysin and chromogranin, focally positive for TTF-1, and weakly positive for racemase. Ki-67 labeled less than 5% with predominant labeling of the larger atypical cells and minimal reactivity in the small cell-like population. In summary, small cell-like change in prostatic intraepithelial neoplasia, intraductal carcinoma, and invasive carcinoma is not associated with small cell carcinoma; shows no immunohistochemical evidence of neuroendocrine differentiation; and likely is not an adverse prognostic feature.

Renal cell carcinoma with clear cell and papillary features.

CONTEXT: The diagnosis of primary renal cell carcinomas (RCCs) with both papillary architecture and cells with clear cytoplasm can be diagnostically challenging for practicing pathologists. The 4 main neoplasms in the differential diagnosis are clear cell RCC, papillary RCC, clear cell papillary RCC, and Xp11 translocation RCC. Accurate diagnosis has both prognostic and therapeutic implications. OBJECTIVE: To highlight the helpful cytomorphologic, immunohistochemical, and cytogenetic features of each of these entities to enable reproducible classification. DATA SOURCES: Published peer-reviewed literature was reviewed, accompanied by the authors' personal experiences. CONCLUSIONS: Key morphologic clues and a focused immunohistochemical panel, including CK7, α-methylacyl coenzyme A racemase (AMACR), TFE3, cathepsin K, and carbonic anhydrase IX (CAIX), now allow most resected RCCs with papillary architecture and clear cells to be accurately classified. In other cases, cytogenetic and molecular findings can establish the diagnosis. Despite these tools, some RCCs with papillary architecture and clear cells do not fit into any of the described entities and currently remain unclassified.

Do adenocarcinomas of the prostate with Gleason score (GS) ≤6 have the potential to metastasize to lymph nodes?

Although rare, there are cases within reported series of men with Gleason score (GS) ≤6 on radical prostatectomies that show pelvic lymph node (LN) metastases. However, there are no studies on whether pelvic LN metastases occur in tumors with GS ≤6 using the International Society of Urological Pathology (ISUP) updated GS system. We performed a search of the radical prostatectomy databases at 4 large academic centers for cases of GS ≤6. Only prostatectomies submitted and embedded in entirety with pelvic LN dissections were included. A combined total of 14,123 cases were identified, of which 22 cases had a positive LN. Histopathologic review of 19 cases (3 cases unavailable for review) showed higher grade than originally reported by the pathologists in all cases. Of the 17 pre-ISUP reviewed cases, 2 were upgraded to 4+3=7 with both cribriform and poorly formed glands. One case was upgraded to 4+3=7 with tertiary pattern 5 displaying cribriform glands, poorly formed glands, and cords of single cells. Eleven cases were upgraded to 3+4=7 with glomeruloid structures and small to large cribriform glands (1 of these also had features of ductal adenocarcinoma). Two cases had tertiary pattern 4 with small cribriform glands. One case had a prominent colloid component that would currently be graded as 4+5=9 because of large cribriform glands and solid sheets of cells within the mucin. Of the 2 post-ISUP cases, 1 demonstrated tertiary pattern 4, and the other showed GS 3+4=7 with irregular cribriform glands. Undergrading is the primary reason for LN positivity with GS ≤6, which has decreased significantly since the adoption of the ISUP grading system in 2005. Of over 14,000 totally embedded radical prostatectomies from multiple institutions, there was not a single case of a GS ≤6 tumor with LN metastases. In contrast to prevailing assumptions, GS ≤6 tumors do not appear to metastasize to LNs. Rather, Gleason pattern 4 or 5, as better defined by the current ISUP updated grading system, is required for metastatic disease.

Xp11 translocation renal cell carcinoma.

Xp11 translocation renal cell carcinoma (RCC) is a group of neoplasms characterised by translocations involving a breakpoint at Xp11.2. The resulting gene fusions involve the TFE3 transcription factor gene and multiple reported genes, including the same one (ASPL) found in the characteristic gene fusion of alveolar soft part sarcoma. Xp11 translocation RCCs likely comprise a significant proportion of paediatric RCCs. While uncommon on a percentage basis in adults, adult cases may outnumber paediatric cases due to the much higher overall incidence of RCC in the adult population. The only known risk factor for its development is prior exposure to chemotherapy. The most distinctive histological pattern is a neoplasm with both clear cells and papillary architecture, often with abundant psammoma bodies. Immunohistochemistry typically reveals minimal reactivity to cytokeratins, epithelial membrane antigen (EMA) or vimentin. The most sensitive and specific immunohistochemical markers for these neoplasms are TFE3 protein and cathepsin-K. Clinical outcome data are still premature at this time. However, children with regional nodal metastases but without haematogenous spread have a favourable short-term prognosis. Adults often present with aggressive tumours with widespread systemic metastases and these patients have a poor clinical outcome. Regardless, the tumour can metastasise decades after its initial presentation, so long-term follow-up is necessary. A recently reported melanotic neoplasm with overt melanin pigment may represent a new subset of TFE3 related cancers.

Influence of perioperative resuscitation status on postoperative spine surgery complications.

BACKGROUND CONTEXT: Restrictive transfusion criteria have led to decreased morbidity and mortality in critically ill patients. Their use has been extended to other patient groups. In adult spine surgery, ongoing postoperative blood losses and soft-tissue trauma may make these patients not appropriate for restrictive transfusion practices. PURPOSE: The purpose of this study was to assess the influence of postoperative hemoglobin (HGB) level and use of packed red blood cells (pRBC) or fresh frozen plasma on postoperative patient morbidity, mortality, and hospital length of stay (LOS). STUDY DESIGN/SETTING: This was a retrospective study in a high-volume tertiary hospital. PATIENT SAMPLE: The sample comprised 300 consecutive patients who underwent spinal surgeries with blood losses of more than 2 L. OUTCOME MEASURES: The outcome measures were postoperative patient morbidity, mortality, and LOS. METHODS: The records of patients who underwent adult spinal surgeries with blood loss of 2 or more L (N=300) were abstracted for patient characteristics, operative characteristics, transfusion, and HGB level over time. Intensive care unit and hospital LOS, discharge location, death, pulmonary embolism, stroke, seizures, surgical site infections (SSI), and myocardial infarctions were noted. Logistic regression analyses (SAS software version 9.2) were used. RESULTS: Twelve (3%) patients had a postoperative HGB level of less than 8 g/dL, 126 (41.3%) had 8 g/dL or more but less than 10 g/dL, and 167 (54.8%) had 10 g/dL or more. There was no significant difference in morbidity or mortality between the two groups with higher HGB levels. Multiple regression analysis revealed that patients with initial postoperative HGB level of less than 8 g/dL were six times more likely to develop SSI (odds ratio 6.37, 95% confidence interval 1.15-35.28). Deep SSI rates were increased with greater postoperative pRBC use (p=.002). Fresh frozen plasma use in the operation room was lower in cases that developed SSI (1.50 vs. 2.69, p=.042). Intensive care unit and ward LOS were longer with increased postoperative blood product use. CONCLUSION: Patients with high blood loss (more than 2 L) during spine surgery who are under-resuscitated (HGB level less than 8 g/dL) have a significant increased risk of SSI.

Intestinal spirochetosis in children: five new cases and a 20-year review of the literature.

Intestinal spirochetosis (IS) is an unusual infection in children, one with no standard therapeutic options. This article reports the findings on 5 new cases in conjunction with a 20-year review of the pediatric literature. The diagnosis of IS in children requires a high degree of suspicion by the physician, as many cases present with abdominal pain, chronic diarrhea, and/or hematochezia associated with a normal endoscopic examination. Silver stains (Dieterle or Whartin-Starry) are the preferred confirmatory stains on tissue sections. Giemsa (Diff-Quik) and periodic acid-Schiff stains may also be of value. Current literature favors the use of metronidazole in adult patients with IS, yet little information is available regarding treatment options in pediatric cases. This review indicates that a macrolide antibiotic with or without metronidazole may represent the best therapeutic choice for children. Further investigations are needed to determine the correlation between IS and coexisting gastrointestinal diseases and/or immunodeficiencies.