Distinct Immunohistochemical Profile Research Articles

Renal-Cell Carcinomas in End-Stage Kidneys

Clear-cell papillary renal-cell carcinoma (CCPC) and acquired cystic kidney disease-associated carcinoma (ACDAC) are neoplasms with distinct morphological characteristics that behave less aggressively than conventional renal-cell carcinomas. End-stage kidney specimens from 61 patients (47 males and 14 females) with 109 renal-cell carcinomas were selected. Papillary renal-cell carcinoma was the most common malignancy (61/109, 56%), followed by CCPC (20/109, 18%). The CCPC showed a papillary or tubular/solid architecture, clear cytoplasm, low nuclear grade, and a distinct immunohistochemical profile (RCC-, vimentin+, CK7+, p504S-). ACDAC displayed a variety of architectural patterns, eosinophilic cytoplasm, high nuclear grade, intratumoral calcium oxalate deposits, and an immunohistochemical profile similar to type 2 papillary renal-cell carcinoma (RCC+, vimentin+, CK7-/+, p504S+). Less than 5% (3/69) of pathologically staged renal-cell carcinomas in end-stage kidneys presented with lymphogenous and/or hematogenous metastases.

Distinctive Immunohistochemical Profile of Penile Intraepithelial Lesions

Several classification schemes for penile precancerous lesions have been proposed, but none of them seems to correlate with the current understanding of penile cancer pathogenesis. Recently, a system, which takes into account morphologic features and purported etiopathogenesis, was proposed, separating penile intraepithelial neoplasia (PeIN) in differentiated and warty/basaloid subtypes. This study was designed to seek an immunohistochemical profile that can be helpful in the classification and differential diagnosis of penile epithelial abnormalities and precancerous lesions using the aforementioned system. The immunohistochemical panel included stains for p16, p53, and Ki-67. For p16 immunostaining, only full-thickness positivity in all epithelial cells was considered as positive; for p53 and Ki-67 immunostaining, patchy or diffuse nuclear positivity above the basal layer was considered as positive. Seventy-four lesions in 59 patients were selected and classified as follows: differentiated PeIN, 34 cases; squamous hyperplasia (SH), 21 cases; basaloid PeIN, 15 cases; and warty PeIN, 4 cases. The mean age of patients was 64 years. Forty-two lesions (56.8%) were located in the glans and 32 (43.2%) in the foreskin. Overexpression of p16 was useful for distinguishing SH from warty/basaloid PeINs (0% vs. 94.7%, P<0.0001) but not SH from differentiated PeINs (0% vs. 5.9%, P=0.519). In addition, p16 allowed the distinction of differentiated and warty/basaloid PeINs (5.9% vs. 94.7%, P<0.0001). Immunohistochemistry results for p53 allowed the separation of SH and differentiated PeIN (9.5% vs. 44.1%, P=0.0078) and SH and warty/basaloid PeIN (9.5% vs. 55.6%, P=0.0042). Ki-67 immunostain was useful for distinguishing SH from differentiated PeIN (52.6% vs. 89.7%, P=0.0062) and SH from PeIN with warty and/or basaloid features (52.6% vs. 100%, P=0.0011). There seems to be a distinctive immunohistochemical profile for associated and precursor epithelial lesions of the penis. SH was p16 and p53 negative, with variable Ki-67 positivity. Differentiated PeIN was p16 negative and Ki-67 positive, with variable p53 positivity. Basaloid and warty PeINs were consistently p16 and Ki-67 positive, with variable p53 positivity. The use of a triple p16/p53/Ki-67 immunohistochemical panel was found to be helpful in the classification, differential diagnosis, and morphologic standardization of penile intraepithelial lesions.

Granular cell tumor of the male breast

A 54-year-old male presented with a painless, hard, irregular lump in his right breast, with fixation to the pectoralis muscle. Mammography and ultrasound showed a 2.5-cm mass suspicious of malignancy. The patient underwent a wide local excision. A 2.5-cm hard, stellate lump was found and sent to the pathologist, which revealed this to be a benign granular cell tumor. Granular cell tumor of the breast is a rare neoplasm, of unknown etiology, which is benign in 98% of cases, but mimics breast cancer, causing challenging diagnostic and therapeutic dilemmas. Traditional imaging techniques do not recognize any feature specific for this tumor. Only excisional biopsy allows the detection of the distinct histological and immunohistochemical profile of the lesion (granular cytoplasm and staining for the S-100 protein). Only local surgical excision is indicated. General and senologist surgeons must be aware of this entity to avoid unnecessary mastectomy or lymphadenectomy.

Atypical sclerosing adenosis of the prostate: a rare mimic of adenocarcinoma

Sclerosing adenosis of the prostate is a benign, small, acinar proliferation in dense spindle cell stroma, with a distinct immunohistochemical profiles. It is incidentally found in about 2% of transurethral resection specimens. The aim was to describe cases with significant cytological atypia mimicking cancer, which have not been previously reported. We describe five cases of sclerosing adenosis with significant cytological atypia, referred to as atypical sclerosing adenosis (ASA), which were initially considered suspicious or diagnostic of adenocarcinoma. Seven other cases of typical sclerosing adenosis were used as controls. All cases of typical and atypical sclerosing adenosis displayed an intact basal cell layer, which was immunoreactive for high-molecular-weight keratin, S100 protein, smooth muscle actin, and prostate-specific antigen, with no differences between ASA and the control group. Alpha-methylacyl-coenzyme A racemase was negative. Three of four cases of ASA had aneuploid DNA content by digital image analysis. All cases of typical sclerosing adenosis were diploid. During a mean follow-up of 33 months (range 5-73 months), none developed recurrence or prostatic cancer. ASA is an unusual small, acinar proliferation of the prostate that may be mistaken for adenocarcinoma, and should be distinguished from other mimics, including atypical adenomatous hyperplasia, mesonephric remnant hyperplasia, and post-atrophic hyperplasia. ASA is a benign lesion and aggressive treatment is unwarranted.

Distinctive immunohistochemical profile of mucinous cystic neoplasms of pancreas, ovary and lung.

Mucinous cystic neoplasms (MCNs) of the pancreas, ovary and lung have a similar histologic appearance. We investigated if immunohistochemical (IHC) studies could help in separating these neoplasms. Twenty-six ovarian MCNs (invasive carcinoma and borderline tumor), 12 pancreatic MCNs (invasive carcinoma, and with moderate or high-grade dysplasia), and 3 pulmonary MCNs (only invasive carcinoma) were retrieved. Our study demonstrated that pancreatic MCNs are positive for CDX-2 (67%), PDX-1 (100%), CK7 (83%) and CK20 (100%), while are negative for CA-125. The IHC profile of ovarian intestinal type MCN is similar to that of pancreatic MCNs, except for lower frequency of CDX-2 expression (29% vs. 67%). Ovarian endocervical like MCNs are positive for CA-125 (100%) and CK7 (100%), while are negative for CDX-2, PDX-1 and CK20. Pulmonary MCNs are positive for CDX-2 (100%), CK7 (100%) and CK20 (100%), while are negative for PDX-1 and CA-125. All tumors are negative for TTF-1, D2-40 and WT-1. We concluded that an IHC panel of CDX-2, PDX-1, CA-125, and CK20 is useful in separating MCNs of the pancreas, ovary and lung.

Variable Antigen Expression in Hepatoblastomas

Hepatoblastoma is a malignant tumor that typically presents as a mass in the liver of a child less than 5 years of age. The diagnosis is usually established by means of a needle core biopsy before the treatment is commenced. The pathologic diagnosis of hepatoblastoma relies on the microscopic identification of typical morphologic features, but these may not be present in a needle core biopsy, and in this setting immunohistochemical staining has an important role in the exclusion of other childhood malignancies. We have studied 12 needle core biopsies from cases of hepatoblastoma, all of which had the diagnosis confirmed by subsequent resection of the tumor, to determine if these tumors show a diagnostic phenotype. The needle biopsies were immunostained with a standard panel of antibodies normally used in the characterization of childhood small round blue cell tumors, with the addition of antibodies directed against alpha-fetoprotein and alpha-1-antitrypsin. Our results indicate that the majority of hepatoblastomas expressed cytokeratins (10/12) and that alpha-1-antitrypsin and alpha-fetoprotein staining were positive in approximately half the cases (5/12 and 7/12, respectively). We also observed frequent expression of antigens normally expressed on other childhood tumors. A significant number of hepatoblastomas (8/12) expressed MIC-2 (CD99) an antigen normally associated with primitive neuroectodermal tumor, 4 cases showed positive staining with the neural-associated antigen NCAM (CD56), and 3 were positive with the neuroblastoma marker NB84. Occasional cases showed expression of the muscle marker desmin (2/12) and 2 cases stained with BCL2. Vimentin expression was seen in 1 case, and a single case also expressed the neural markers PGP9.5 and neurone-specific enolase. In all cases, the tumor cells were negative with CD45, WT1, and S-100. These findings indicate that the primitive cells in hepatoblastoma have a variable immunophenotype and can express antigens normally seen in other childhood malignancies. In the clinical setting of the differential diagnosis of childhood abdominal mass, hepatoblastoma shows no distinct immunohistochemical profile, and the diagnosis requires a combination of the clinical, imaging, and pathologic findings.

Ameloblastoma, calcifying epithelial odontogenic tumor, and glandular odontogenic cyst show a distinctive immunophenotype with some myoepithelial antigen expression

Odontogenic neoplasms have some morphologic overlap with salivary gland neoplasms, many of which show myoepithelial differentiation. In the 1980s, an ultrastructural study identified a population of myoepithelial-like cells in calcifying epithelial odontogenic tumor. Myoepithelial derived tumors have since been shown to have distinct immunohistochemical profiles. We examined a series of odontogenic neoplasms, including 11 ameloblastomas, four calcifying epithelial odontogenic tumors, five glandular odontogenic cysts (GOCs), and five keratocystic odontogenic tumors with a panel of myoepithelial-associated immunohistochemical stains. We also assessed representative control examples of oral mucosa, odontogenic rests, and dentigerous cysts. All of the neoplastic and non-neoplastic oral epithelium-derived entities share a p63-positive, high molecular weight cytokeratin (CK5/6)-positive immunophenotype. Calponin reactivity was at least focally present in two of four calcifying epithelial odontogenic tumors, three of five GOCs, and 10 of 11 ameloblastomas; the sole completely non-reactive ameloblastoma represents a lung metastasis. One case of calcifying epithelial odontogenic tumor was focally positive for glial fibrillary acidic protein. However, other more definitive markers of myoepithelial differentiation, including S-100 and smooth muscle actin, were negative. Two of three calcifying epithelial odontogenic tumors and five of five GOCs were also positive for a low molecular weight cytokeratin (CK7). Ameloblastomas, GOCs, and calcifying epithelial odontogenic tumors show a distinctive immunophenotype which overlaps with that of myoepithelial-derived salivary gland neoplasms but does not provide definitive support for myoepithelial differentiation.

Human papillomavirus (HPV) related carcinomas of the upper aerodigestive tract.

Epidemiologic, clinical, morphologic and molecular evidence show that high risk HPV, particularly type 16, is a prerequisite for some carcinomas of the upper aerodigestive tract (UADT), particularly tonsil and base of tongue. Sexual transmission is an important mode of infection while tobacco use and excessive drinking are not considered risk factors. HPV + tumors are distinct clinically and pathologically. They are more common in young patients (<40 years) with a male to female ratio of 4:1. They usually present as a small or occult primary tumor with advanced neck disease. Microscopically they are non-keratinizing squamous cell carcinomas with basaloid features, excessive mitosis and comedo type necrosis. The tumors have a distinct immunohistochemical profile characterized by strong and diffuse p16 reactivity, low or negative p53 staining and high Ki67 labeling scores. HPV + carcinomas are more radio-sensitive and have a better prognosis than the classical keratinizing SCC of the UADT. An anti-HPV vaccine has recently been made available for prevention of cervical cancer. The impact of the vaccine on the prevalence of HPV related carcinomas of the UADT is currently not known but likely beneficial.

Differential expression of biomarkers in lung adenocarcinoma: a comparative study between smokers and never-smokers

Background: Non-small-cell lung cancer arising in never-smokers is usually of adenocarcinoma subtype. The oncogenic pathway of such tumors is poorly understood. To better define the biological characteristics of these tumors, we have compared the expression of a panel of epidermal growth factor receptor (EGFR)-related biomarkers in lung adenocarcinomas from smokers versus those in never-smokers.Patients and methods: Using immunohistochemical analysis, we retrospectively analyzed EGFR, pAKT, PTEN, Ki-67, p27 and hTERT expression in specimens from 190 patients with completely resected lung adenocarcinomas (43 never-smokers and 147 smokers). These analyses were performed on tissue microarrays.Results: EGFR expression was higher in tumors from smokers (P < 0.01), while pAKT was overexpressed mainly in tumors from never-smokers (P = 0.01). As expected, the tumors from smokers presented a higher expression of Ki-67 and a more frequent loss of expression of p27 (P < 0.01). In a multivariate model, two biological factors (p27 and Ki-67) and two clinical factors (age and sex) showed independent significant correlation with never-smoking status.Conclusions: Lung adenocarcinomas in never-smokers have a very distinct immunohistochemical expression profile of EGFR-related biomarkers as compared with lung adenocarcinomas in smokers. High levels of EGFR and Ki-67 are observed in smokers, while never-smokers are characterized by high levels of pAKT and p27.

Expression of Melan-A and Ki-67 in Desmoplastic Melanoma and Desmoplastic Nevi

Desmoplastic melanoma (DMM) is an uncommon melanoma variant with a distinct morphology, including a prominent spindle cell component with fibrosis, as well as a distinct immunohistochemical profile. Histologically, the spindle cell component of DMM can be confused with sclerotic/desmoplastic nevi, nonpigmented blue nevi, scar, and neural tumors. The histological distinction between sclerotic/desmoplastic/blue nevi and DMM using standard light microscopic techniques can be exceedingly subtle. Therefore, we investigated whether immunohistochemical staining for Melan-A and Ki-67 expression can be used to discriminate these lesions, distinguishing between epithelioid and spindle cell compartments of the lesions. Fifty cases of DMM and 13 cases of sclerotic/desmoplastic/blue nevi were identified. Standard immunohistochemical techniques were used with antibodies towards HMB-45, Melan-A (A103), and Ki-67; 43 of 50 DMM cases were available for staining with Melan-A, 42 of 50 for HMB-45, and 31 of 50 cases were stained with Ki-67. All 13 nevi were stained for Melan-A and 8 for Ki-67. Immunoreactivity to Ki-67 antibody was scored as 0 to 5%, 6 to 10%, 11 to 30%, or greater than 30% positive tumor cells. Only 3 of 43 and 3 of 42 of spindle cell compartments of DMMs were positive for Melan-A and HMB-45, respectively. Focal staining of epithelioid cells in the junctional component or superficial dermis was observed in 33% (14/43). In contrast, 100% of the 13 nevi were strongly positive for Melan-A (P < 0.001). Seventeen melanomas (55%) were 0 to 5% positive for Ki-67, five (16%) fell into the 6 to 10% category, three (10%) were between 11 and 30%, and six (19%) were at least focally greater than 30% positive. All 8 nevi (100%) had less than 5% positive cells for Ki-67 (P = 0.02), with only 2 cases having more than 2% positive cells. The sclerotic/desmoplastic and hypopigmented blue nevi were uniformly positive for Melan-A, while the vast majority of DMM were negative in their spindle cell compartments. Melan-A is very useful in distinguishing between DMM and sclerotic nevi. Ki-67 appears to be an inconsistent marker for DMM. However, a high labeling index (over 5%) may be used as a clue in diagnosing DMM.

New developments in the pathology of skull base tumors.

As an anatomical interface between various tissues, the skull base harbors an exceptionally broad variety of neoplasms, some of which pose a major challenge for surgical pathology. The characterization of distinct immunohistochemical expression profiles and the identification of molecular genetic alterations associated with different tumor entities have significantly advanced this field. The new World Health Organization (WHO) classification of tumors of the nervous system lists 15 histopathological variants of meningioma. Of clinical importance are those entities that carry an increased risk of recurrence and a poor prognosis, i.e., the atypical meningioma (WHO grade II), clear-cell meningioma (WHO grade II), chordoid meningioma (WHO grade II), rhabdoid meningioma (WHO grade III), papillary meningioma (WHO grade III), and anaplastic meningioma (WHO grade III). Diagnostic criteria for atypical and anaplastic meningioma variants have now been stringently defined. The differential diagnosis of meningiomas includes hemangiopericytoma, hemangioblastoma, solitary fibrous tumor, sarcomas, and chordoid neoplasms. Recent data highlight the importance of distinguishing chordoma and chondrosarcoma of the skull base since chondrosarcomas show a significantly better clinical outcome. Among the less common, aggressive tumor entities in this anatomical region, infiltrating pituitary adenoma/pituitary carcinoma, superficial malignant gliomas, rhabdomyosarcoma, olfactory neuroblastoma, various sarcomas, and malignant lymphoma must be considered. Profiles of molecular genetic alterations have been established for several of these neoplasms and may facilitate the differential diagnosis. This review summarizes recent developments in the histopathological characterization, classification, and molecular pathology of neoplasms arising at the skull base.

Lipomatous hemangiopericytoma: a morphologically distinct soft tissue tumor.

Hemangiopericytoma of soft tissue is a controversial pathologic entity. The relative nonspecificity of the characteristic branching capillary pattern and cytologic features of the constituent cells, in addition to the lack of a distinct immunohistochemical staining profile, has resulted in uncertainty and a lack of consensus regarding this subgroup of tumors. Notwithstanding the doubt surrounding this entity, a morphologically unique variant, designated lipomatous hemangiopericytoma, was reported in 1995. To our knowledge, there have been no further reports of these tumors since the original description. We describe a lipomatous hemangiopericytoma that arose within the thigh of a 41-year-old woman. The tumor presented as a slowly enlarging, minimally tender, pulsatile mass. The tumor was completely excised and was found to be composed of an admixture of typical hemangiopericytoma and predominantly mature adipose tissue. Unlike previous descriptions of this entity, the current example exhibited a full range of adipocyte differentiation, including many multivacuolated adipocytes of variable size with characteristic nuclear scalloping (lipoblast-like cells). The mitotic count was less than 2 per 10 high-power fields examined. The clinical course has been benign during the short follow-up period. We discuss the pathologic features, including the immunohistochemical staining profile and ultrastructural appearance of this distinctive tumor, and briefly discuss the relationship between hemangiopericytoma and solitary fibrous tumor of soft tissue, a neoplasm with many clinical and pathologic similarities.

Lipomatous hemangiopericytoma: a morphologically distinct soft tissue tumor.

Hemangiopericytoma of soft tissue is a controversial pathologic entity. The relative nonspecificity of the characteristic branching capillary pattern and cytologic features of the constituent cells, in addition to the lack of a distinct immunohistochemical staining profile, has resulted in uncertainty and a lack of consensus regarding this subgroup of tumors. Notwithstanding the doubt surrounding this entity, a morphologically unique variant, designated lipomatous hemangiopericytoma, was reported in 1995. To our knowledge, there have been no further reports of these tumors since the original description. We describe a lipomatous hemangiopericytoma that arose within the thigh of a 41-year-old woman. The tumor presented as a slowly enlarging, minimally tender, pulsatile mass. The tumor was completely excised and was found to be composed of an admixture of typical hemangiopericytoma and predominantly mature adipose tissue. Unlike previous descriptions of this entity, the current example exhibited a full range of adipocyte differentiation, including many multivacuolated adipocytes of variable size with characteristic nuclear scalloping (lipoblast-like cells). The mitotic count was less than 2 per 10 high-power fields examined. The clinical course has been benign during the short follow-up period. We discuss the pathologic features, including the immunohistochemical staining profile and ultrastructural appearance of this distinctive tumor, and briefly discuss the relationship between hemangiopericytoma and solitary fibrous tumor of soft tissue, a neoplasm with many clinical and pathologic similarities.