Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression.

NKX3.1 is a prostate-specific homeobox gene located on chromosome 8p21. In the mouse, Nkx3.1 has growth-suppressive and differentiating effects on prostatic epithelium. Mutations of the coding region of NKX3.1 were not found in human prostate cancer, failing to support the notion that NKX3.1 was a tumor suppressor gene. To study the expression o NKX3.1 protein in human tissues and prostate cancer, we derived a rabbit antiserum against purified recombinant NKX3.1. Among normal human tissues, NKX3.1 expression was seen in testis, in rare pulmonary mucous glands, and in isolated regions of transitional epithelium of the ureter. NKX3.1 was uniformly expressed in nuclei of normal prostate epithelial cells in 61 histological sections from radical prostatectomy specimens. We analyzed 507 samples of neoplastic prostate epithelium, most of which were contained on a tissue microarray that contained samples from different stages of prostatic neoplasia. We observed complete loss of NKX3.1 expression in 5% of benign prostatic hyperplasias, 20% of high-grade prostatic intraepithelial neoplasias, 6% of T1a/b samples, 22% of T3/4 samples, 34% of hormone-refractory prostate cancers, and 78% of metastases. Our data show that NKX3.1 expression is highly, but not exclusively, specific for the prostate. Loss of NKX3.1 expression is strongly associated with hormone-refractory disease and advanced tumor stage in prostate cancer (P < 0.0001).

Recommendations for the reporting of tumors of the adrenal cortex and medulla. Association of Directors of Anatomic and Surgical Pathology.

The Association of Directors of Anatomic and Surgical Pathology has developed recommendations for the surgical pathology report for common malignant tumors. The recommendations for tumors of the adrenal cortex and medulla are reported herein.

Pigmented ("black") extraadrenal paraganglioma.

A pigmented ("black") extraadrenal paraganglioma was discovered incidentally in a 57-year-old woman during ultrasonography. The tumor was located in the retroperitoneum near the superior border of the right kidney. Results of preoperative fine-needle aspiration and intraoperative frozen sectioning of the resected jet-black tumor (13 cm in diameter, 225 g) were both interpreted as suspicious for malignant melanoma. Histomorphology and immunohistochemistry were diagnostic for paraganglioma. Electron microscopy showed numerous dense-core neurosecretory-type granules, as well as abundant, larger pleomorphic electron-dense granules; most were consistent with lipofuscin or neuromelanin. No melanosomes or premelanosomes were identified. Histochemical stains showed that the pigment most likely is neuromelanin, a nonenzymatic or oxidative waste product of catecholamine metabolism. Eighteen other examples of pigmented paragangliomas have been reported in various sites in the English literature during the last 12 years; most indicate the presence of melanosomes or premelanosomes using electron microscopy, whereas in a minority of cases the pigment has not been characterized rigorously. Common embryogenesis from neural crest may help explain the overlapping phenotype of melanocytes and cells of paraganglioma.

Solitary fibrous tumors: a series of lesions, some in unusual sites.

Solitary fibrous tumor (SFT) is a rare neoplasm that, in addition to its classic presentation as a pleural-based mass, can also be encountered in unusual sites. The main difficulty in making the diagnosis of SFTs results from the unfamiliarity with its diverse clinical and pathologic features. This series of SFTs, some with unusual clinicopathologic presentation, included nine women and two men, ranging in age from 28 years to 74 years (five in pleura, one in lung parenchyma, one in breast, and four in mediastinum). The tumors were locally excised in eight cases and were resected along with portions of lung parenchyma in three. A panel of immunohistochemical stains was used to characterize these tumors. They were all vimentin-positive and, with the exception of one case, CD34-positive. Tumors were negative with antibodies directed against cytokeratin, factor VIII-related antigen, S-100 protein, muscle-specific actin, and smooth-muscle actin. Various diagnoses were initially rendered for these clinically and pathologically diverse lesions by the examining pathologists. Awareness of the various gross and microscopic patterns of these tumors, the possibility of occurring in unusual sites, and the use of immunohistochemical stains, particularly CD34, should eliminate most of the difficulties in arriving at a correct diagnosis. One patient died of metastatic breast cancer; all other patients were alive and well with a median follow-up of 17 months.

MDM2 amplification, P53 mutation, and accumulation of the P53 gene product in malignant fibrous histiocytoma.

Fifty-two cases of malignant fibrous histiocytoma (MFH) were evaluated for amplification of the MDM2 gene, mutation of the P53 gene, accumulation of the P53 gene product, and their relation to disease-free and overall survival. All tests were carried out on formalin-fixed, paraffin-embedded tissue samples. Amplification of the MDM2 gene was detected in 15 of 52 cases (29%). Six of 52 cases (12%) demonstrated abnormalities of the P53 gene. Sequence analysis detected point mutations in four cases and a 1-base pair deletion in one case, whereas differential polymerase chain reaction (dPCR) indicated that the P53 gene had been entirely deleted in one case. Eight of 52 cases (15%) demonstrated staining for the P53 protein in >10% of tumor cells. The presence of MDM2 amplification did not have a significant effect on either disease-free or overall survival. Patients with accumulation of the P53 gene product did not differ in disease-free or overall survival from patients without P53 accumulation. Survival also was not significantly different in patients with genetic aberration in P53. However, when the patients were stratified by histologic grade, the results indicated that patients with alterations in the P53 gene may have shorter overall survival.

Cardiac papillary fibroelastoma: an immunohistochemical investigation and unusual clinical manifestations.

Cardiac papillary fibroelastoma (CPF) is a morphologically distinctive, but rare, cardiac lesion that is usually found incidentally at autopsy or during open heart surgery. Because of improved diagnostic imaging techniques, the premortem or preoperative diagnosis of CPF is becoming more frequent. The histogenesis of CPF, however, remains controversial. Herein we report an immunohistochemical investigation of 11 cases of CPF; two cases showed unusual embolization phenomena, including one with histologically documented pulmonary arterial embolism. For comparison, nine cardiac myxomas (CMs) and eight examples of organizing thrombi were also studied. Immunohistochemical markers included keratin, vimentin, collagen type IV, muscle-specific actin, desmin, factor VIII-related antigen, CD34, and S-100 protein. The cells covering the surface of both CPFs and CMs were positive for vimentin, factor VIII-related antigen, and CD34, in keeping with their presumed vascular endothelial origin. Interestingly, the surface lining cells were also positive for S-100 protein in all CPF and in eight of nine CMs. In CPF, collagen type IV showed multilayered linear staining beneath the surface that was virtually identical to the staining pattern for elastic tissue. The major immunophenotypic difference between CPF and CM is the frequent presence of muscle-specific actin in the stellate cells of the stroma in CM but not in CPF. Although this study did not clarify whether CPF is a hamartomatous, neoplastic, or reparative process, it demonstrated active participation of the surface endothelial lining cells with excessive formation of basal membrane material in the formation of CPF.

Primary lymphoma of the appendix. Case report and review of the literature.

Malignant lymphomas comprise 1-4% of the malignant neoplasms of the gastrointestinal tract, but appendiceal lymphomas are exceedingly rare. Herein is presented a case of a well differentiated lymphocytic lymphoma of the appendix found incidentally at hernia repair. Forty-six cases of appendiceal lymphoma have been reported since 1898 with a mean patient age of 25.7 years. Thirty-one patients presented with right lower quadrant pain, and a mass was an incidental finding in five. Of the 46 cases, follow-up was possible in 28. There were four deaths within 30 days of the operation and five deaths within 1 year. Although extensive follow-up is limited, there have been only two reported deaths secondary to primary appendiceal lymphoma since 1945 and these two cases are discussed in detail. Based on this extensive review, appropriate recommendations are made.

Immunohistochemical detection of neuroblastomatous foci in composite adrenal pheochromocytoma-neuroblastoma.

To determine if immunohistochemistry might aid in the identification of neuroblastomatous foci in composite adrenal tumors, the authors analyzed two examples of composite adrenal pheochromocytoma-neuroblastoma, 18 pure pheochromocytomas, and six pure neuroblastomas using peanut agglutinin and a panel of antibodies directed against neuroendocrine and neural-associated antigens. Pure pheochromocytoma had the following immunopositivity: vimentin 14/18, chromogranin 18/18, synaptophysin 18/18, S100 protein 0/18 (tumor cells), neurofilament 14/18, J1 beta-tubulin (J1) 18/18, microtubule-associated protein-2 13/18, glial fibrillary acidic protein 13/18, and peanut agglutinin 17/18. Pure neuroblastoma reacted positively as follows: vimentin 0/6, chromogranin 5/6, synaptophysin 4/6, S100 protein 0/6 (tumor cells), neurofilament 5/6, J1 6/6, microtubule-associated protein-2 6/6, glial fibrillary acidic protein 1/6, and peanut agglutinin 6/6. Each component of both composite tumors reacted similarly to the pure neoplasms. Although the frequency of positive staining was similar for pheochromocytoma and neuroblastoma, the intensity and pattern differed for several antigens. Pheochromocytoma was diffusely positive for synaptophysin and chromogranin, whereas staining was focal and punctate in neuroblastoma. Microtubule-associated protein-2, J1, and neurofilament antibodies highlighted the fibrillar background of neuroblastoma, which pheochromocytoma lacked. Pheochromocytoma contained focal, ball-like immunoreactivity for glial fibrillary acidic protein and vimentin, which was absent in neuroblastoma. These immunohistochemical distinctions can assist the clinically important recognition of neuroblastomatous foci in composite adrenal pheochromocytoma-neuroblastoma.

Diffuse hemorrhagic gastroenteropathy: report of a new entity.

An apparently novel entity, diffuse hemorrhagic gastroenteropathy (DHG), in a 70-year-old female who had an unremitting course of chronic gastrointestinal blood loss for 3 years requiring transfusion of more than 200 units of packed red blood cells over this period is reported here. Endoscopy showed diffusely hemorrhagic mucosa in the stomach, duodenum, and small bowel. Full-thickness biopsy of the stomach and small intestine revealed luminal narrowing of capillaries and post-capillary venules within the lamina propria due to swelling and some proliferation of the endothelial cells with margination and emigration by neutrophils as well as partial occlusion of some vessels by fibrin thrombi. DHG may represent a new entity characterized by mucosal hemorrhage due to local mucosal ischemia of the gastrointestinal tract secondary to a small vessel "vasculopathy" apparently restricted to this site.

Solitary cavernous hemangioma of small intestine. Case report and literature review.

We describe a 14-year-old boy with a solitary cavernous hemangioma in the proximal small intestine that caused recalcitrant iron deficiency anemia beginning at 3 years of age. After a number of attempts to ascertain the cause of the anemia were unsuccessful, the vascular tumor was ultimately diagnosed in the jejunum, approximately 80 cm distal to the ligament of Treitz. We discuss the differential diagnoses of vasoformative intestinal lesions and review the literature on enteric cavernous hemangiomas in childhood.

Late occurrence of malignancy following resection of a histologically mature sacrococcygeal teratoma. Report of a case and literature review.

A sacrococcygeal adenocarcinoma is reported in a male patient nearly 40 years old following resection of a histologically mature sacrococcygeal teratoma. The adenocarcinoma arose within soft tissue of the presacral area and residual coccyx and extensively invaded the coccygeal stump that had not been removed in toto with the teratoma during initial surgery at 2 months of age. The patient died nearly 2 years later with local and regional recurrence of tumor and metastases to lymph nodes, liver, lung, bone, and brain. At autopsy there was no evidence of origin from deep internal organs such as the stomach, pancreas, or other sites. Brief comments are made about malignant tumors complicating sacrococcygeal teratomas in both the pediatric age group and adults, and attention is focused on other lesions entering into the differential diagnosis, particularly retrorectal cyst/hamartoma or tailgut cysts. This case underscores an extremely rare but potentially fatal outcome of a patient with sacrococcygeal teratoma.

"Signet Ring" sinus histiocytosis mimicking metastatic adenocarcinoma: report of two cases with immunohistochemical and ultrastructural study.

The axillary lymph nodes from two patients with invasive breast carcinoma showed "signet ring" histiocytosis with sinusoidal distribution of cells having prominent cytoplasmic vacuolization which simulated metastatic adenocarcinoma. Immunohistochemical studies confirmed the histiocytic nature of the signet ring cells and eliminated the possibility of metastatic adenocarcinoma. Electron microscopy in one case revealed lipid within the cytoplasmic vacuoles. The etiology of this reactive change is unknown; however, a history of previous surgery involving the chest wall may be causally related with disruption of adipose tissue. Prior to ipsilateral mastectomy both patients had undergone a contralateral mastectomy for mammary carcinoma. Signet ring sinus histiocytosis is a reactive sinusoidal proliferation that can mimic metastatic carcinoma, but close inspection will usually reveal the histiocytic nature of the cells.

Amebiasis complicating carcinomas: a diagnostic dilemma.

Two black African women and one black American man had carcinomas of cervix, perineum, and sigmoid colon, respectively. In each of these patients, trophozoites of Entamoeba histolytica had invaded the surface of the tumor, and in some areas had invaded more deeply into the stroma between the tumor cells. Although it is well known that cutaneous amebiasis of anus, penis, vulva, and cervix can mimic squamous cell carcinoma, it may be, perhaps, less well known that carcinomas at these sites may be colonized by trophozoites of E. histolytica. In patients with amebiasis but without an associated carcinoma, a correct diagnosis of amebiasis spares the patient unnecessary and sometimes mutilating surgery. But a diagnosis of amebiasis, when there is an unrecognized underlying carcinoma, delays effective treatment of the carcinoma. A smear that establishes a diagnosis of cutaneous amebiasis, therefore, should be followed by biopsy to exclude or confirm an underlying carcinoma.

Primary osteosarcoma of the uterus: report of a case with immunohistochemical study.

A 63-yr-old female presented with uncontrollable uterine bleeding. Pathological evaluation revealed a uterine mesenchymal neoplasm which histologically represented a primary osteosarcoma. Immunohistochemistry was utilized to help support the diagnosis. The English literature regarding this rare uterine neoplasm is briefly reviewed.

Cytokeratin expression in adrenocortical neoplasia: an immunohistochemical and biochemical study with implications for the differential diagnosis of adrenocortical, hepatocellular, and renal cell carcinoma.

The immunostaining patterns of adrenocortical tumors are not clearly defined, primarily due to their inconsistent expression of cytokeratins (CK). To address this issue and to investigate whether adrenocortical tumors can be immunohistochemically differentiated from histologically similar tumors arising from the kidney and liver, we studied four normal adrenal glands, two adrenocortical adenomas (ACAs), 31 adrenocortical carcinomas (ACCs), 37 renal cell carcinomas (RCCs), and 33 hepatocellular carcinomas (HCCs) with anti-CK antibodies AE1, CAM 5.2, UCD/PR10.11, 35BH11, PKK1, and Ks19.1, as well as antibodies to vimentin (VIM), epithelial membrane antigen (EMA), and HMFG-2. Normal adrenal cortical cells showed variable staining with all anti-CK antibodies on fixed and frozen sections. In contrast, only one of two fixed ACAs stained with a single anti-CK, although both neoplasms reacted with multiple anti-CK antibodies on frozen sections. Similarly, 20 of 31 fixed ACCs contained VIM, but only one tumor stained for CK; frozen sections of this and another, previously negative tumor, however, stained with most of the anti-CK antibodies tested. One-dimensional Western immunoblot analysis confirmed the presence of CKs 18 and 19 in two examples of normal adrenal cortex, one ACA, and the ACC immunohistochemically positive on fixed and frozen sections, with CK 19 identified in the ACC that was positive on frozen section alone. All fixed HCCs and most RCCs stained with multiple anti-CK antibodies (33 and 34 cases, respectively), with a proportion of tumors positive for VIM (six and 22 cases, respectively), EMA (seven and 30 cases, respectively), and HMFG-2 (15 and 28 cases, respectively). The results suggest that CK expression is diminished in most adrenocortical tumors to levels too low to be recognized following the deleterious effects of fixation. While the immunohistochemical absence of CK, EMA, and HMFG-2 in fixed sections in the majority of ACCs is distinctive, sufficient phenotypic overlap exists such that differentiation between RCC and HCC may not be possible in an individual case.

Heterotopia of gastric mucosa and liver involving the gallbladder. Report of two cases with literature review.

Two cases of heterotopic tissue involving the gallbladder are presented (one gastric mucosa, the other liver), and the relevant literature is reviewed highlighting problems in differential diagnosis and complications, particularly with regard to gastric mucosal heterotopia. A firm diagnosis of gastric heterotopia is based on the presence of fundic mucosa replete with parietal and chief cells; a clear distinction from intestinal metaplasia should be made, but at times may be difficult. Potential complications include mucosal ulceration, obstruction, and hemorrhage. Of 39 patients presented, about half were 30 years of age or younger, and only nine have had calculi noted in the cholecystectomy specimen. Heightened awareness of gastric heterotopia with separation of smooth-muscle bundles may help to avoid a malignant diagnosis. Hepatic tissue involving the gallbladder that is completely separate from the main part of the liver is an even rarer form of heterotopia that should be distinguished from an accessory lobe.