The utility of immunohistochemistry for providing genetic information on tumors.

With advances in immunohistochemical technology and growing knowledge of the molecular genetics of tumors, immunohistochemistry is playing an increasingly important role in providing genetic information for tumors. Specific chromosomal translocations can be demonstrated through detection of the protein product of one of the genes involved in gene fusion (such as BCL2, cyclin D, and ALK). Some mutations can be detected by (1) aberrant localization of the protein product (such as ß-catenin and nucleophosmin), (2) abnormal accumulation of the protein product as a result of stabilization of the protein (such as p53), and (3) mutation-specific antibodies directed against the mutant protein (such as isocitrate dehydrogenase gene R132H mutation, epidermal growth factor receptor gene L858R and exon 19 deletion mutations, and BRAF gene V600E mutation). Gene deletion or loss of function can be demonstrated by the loss of immunostaining for the protein product (such as mismatch repair proteins in microsatellite-unstable tumors, E-cadherin in lobular carcinoma of the breast, and INI1 in rhabdoid tumors, atypical teratoid/rhabdoid tumors, and epithelioid sarcomas). Gene amplification can be demonstrated by overexpression of the protein product (such as HER2 in breast and gastric cancers, and MDM2 or CDK4 in well-differentiated/dedifferentiated liposarcomas). Viruses associated with tumors can be demonstrated directly (such as Epstein-Barr virus latent membrane protein-1 in Hodgkin lymphomas, human herpesvirus 8 in Kaposi sarcomas, and Merkel cell polyomavirus in Merkel cell carcinomas) or by a surrogate marker (such as p16 in human papillomavirus infection). In this review, examples are given to illustrate the principles and pitfalls of these applications.

Spontaneous complete regression of gastric large-cell neuroendocrine carcinoma: mediated by cytomegalovirus-induced cross-autoimmunity?

Spontaneous regression of malignant tumour is a rare phenomenon. This report describes such an occurrence in a gastric large cell neuroendocrine carcinoma of a 77-year-old man. The patient presented with dyspepsia, and biopsy of the fungating mass in the cardia showed a high grade neuroendocrine carcinoma. The pre-operative biopsy taken after 3 months showed chronic inflammation and cytomegalovirus inclusions, but no tumour. In the gastrectomy specimen, no residual tumour was found. Instead, there were foamy histiocytes, chronic inflammatory cells and fibrovascular tissue splitting apart the muscularis propria. In addition, there was ganglionitis involving the myenteric plexus, even in areas of the stomach away from the inflamed site. Chemotherapy, radiotherapy or alternative medicine (including herbal medicine) had not been given. We postulate that cytomegalovirus infection initiated a cross-autoimmune reaction against neuronal cells, and this reaction "unintentionally" eliminated the carcinoma cells which also expressed neural antigens.

Nuclear inclusions and pseudoinclusions: friends or foes of the surgical pathologist?

Abnormal substances in the nuclei that can be observed by light microscopy are often broadly referred to as nuclear inclusions. Although their recognition in the appropriate clinicopathological settings can aid in the diagnosis of some disease entities and tumor types, they can also be a source of error. There are 2 morphologically distinct types of inclusions with different mechanisms of formation and diagnostic significance, including bona fide nuclear inclusions and nuclear pseudoinclusions. Bona fide nuclear inclusions result from accumulation in the nuclei of viral particles, cytoplasmic materials (such as surfactant, immunoglobulin, and glycogen), biotin, nuclear lamins, or polyglutamine. Some of them are diagnostically helpful, such as surfactant inclusion, which can support the pulmonary origin of an adenocarcinoma, whereas others may be misleading, such as biotin inclusion, which can be mistaken for herpes infection. Nuclear pseudoinclusions, which represent invaginations of cytoplasm into the nucleus, are delimited by the nuclear membrane. Although not totally specific, they are particularly common in papillary thyroid carcinoma, meningioma, and usual ductal hyperplasia of the breast and hence may aid in the diagnosis of these entities. Nuclear pseudo-pseudoinclusions, which are artefactual bubbles in the nuclei that mimic nuclear pseudoinclusions or clear nuclei, can lead to misdiagnosis of follicular adenoma or hyperplastic nodule as papillary thyroid carcinoma.

Sporadic hemangioblastoma of the kidney: an underrecognized pseudomalignant tumor?

Hemangioblastoma is a benign tumor that can occur sporadically, or in association with von Hippel-Lindau disease in approximately one-quarter of the cases. Only exceptionally does it occur outside the central nervous system. This report describes 2 cases of sporadic renal hemangioblastoma, with 1 patient presenting with hematuria and polycythemia, and the other low back pain. Histologically, the tumors were circumscribed, and composed of sheets of large polygonal cells traversed by arborizing thin-walled blood vessels. Many of the tumor cells showed pleomorphic nuclei, but the mitotic figures were rare. The cytoplasm was eosinophilic, and occasionally finely vacuolated indicating the presence of lipid. The diagnosis of hemangioblastoma was confirmed by negative immunostaining for cytokeratin, and positive staining for α-inhibin, S100, and neuron-specific enolase. This benign neoplasm which can be mistaken for various malignancies such as renal cell carcinoma, epithelioid angiomyolipoma, adrenal cortical carcinoma, and paraganglioma, deserves wider recognition for its occurrence as a primary renal tumor.