Kvetoslava Michalova - Academia.edu (original) (raw)

Papers by Kvetoslava Michalova

We present a series of 16 salivary gland tumors with histomorphologic and immunohistochemical fea... more We present a series of 16 salivary gland tumors with histomorphologic and immunohistochemical features reminiscent of secretory carcinoma of the breast. This is a hitherto undescribed and distinctive salivary gland neoplasm, with features resembling both salivary acinic cell carcinoma (AciCC) and lowgrade cystadenocarcinoma, and displaying strong similarities to breast secretory carcinoma. Microscopically, the tumors have a lobulated growth pattern and are composed of microcystic and glandular spaces with abundant eosinophilic homogenous or bubbly secretory material positive for periodic acid-Schiff, mucicarmine, MUC1, MUC4, and mammaglobin. The neoplasms also show strong vimentin, S-100 protein, and STAT5a positivity. For this tumor, we propose a designation mammary analogue secretory carcinoma of salivary glands (MASC). The 16 patients comprised 9 men and 7 women, with a mean age of 46 years (range 21 to 75). Thirteen cases occurred in the parotid gland, and one each in the minor salivary glands of the buccal mucosa, upper lip, and palate. The mean size of the tumors was 2.1 cm (range 0.7 to 5.5 cm). The duration of symptoms was recorded in 11 cases and ranged from 2 months to 30 years. Clinical follow-up was available in 13 cases, and ranged from 3 months to 10 years. Four patients suffered local recurrences. Two patients died, 1 of them owing to multiple local recurrences with extension to the temporal bone, and another owing to metastatic dissemination to cervical lymph nodes, pleura, pericardium, and lungs. We have shown a t(12;15) (p13;q25) ETV6-NTRK3 translocation in all but one case of MASC suitable for analysis. One case was not analyzable and another was not available for testing. This translocation was not found in any conventional salivary AciCC (12 cases), nor in other tumor types including pleomorphic adenoma (1 case) and low-grade cribriform cystadenocarcinoma (1 case), whereas ETV6-NTRK3 gene rearrangements were proven in all 3 tested cases of mammary secretory carcinoma. Thus, our results strongly support the concept that MASC and AciCC are different entities.

Laboratory Investigation

Results: Strictures were characterized by a mean 2.3-fold increase in overall mural thickness and... more Results: Strictures were characterized by a mean 2.3-fold increase in overall mural thickness and by 2.6and 1.8-fold increases in the areas occupied by smooth muscle and collagen, respectively. Approximately half the increase in wall thickness was attributable to a mean 22-fold expansion of the muscularis mucosae (MM) from 2.2±1.6% to 16.5±10.1% of the total mural thickness and the remainder of the increase to expansions of the internal layer of muscularis propria (MP-I) and submucosa (SM). The external layer of the muscularis propria was similar in thickness and composition to controls. Microscopically, the expanded MM featured (1) architectural disarray, (2) myocyte hyperplasia and (3) pericellular collagen fibers. In contrast, the thickened MP-I featured (1) preserved muscular architecture, (2) no pericellular collagen fibers, and (3) widened intramuscular septa with increased collagen. The SM exhibited fibrosis in continuity with the intramuscular septa. Additionally, submucosal arteries and veins frequently exhibited eccentric fibromuscular hyperplasia which was polarized toward the mucosa. Conclusions: Stricturing Crohn’s ileitis is characterized by distinctive fibromuscular alterations in the individual intestinal wall layers. These alterations may reflect differential mesenchymal responses to luminal-based and transmural inflammatory stimuli. The implications for stricture pathogenesis may help guide progress toward prevention and therapy.

Annals of Diagnostic Pathology

Clear cell renal cell carcinoma (ccRCC), the most common histologic subtype of RCCs, demonstrates... more Clear cell renal cell carcinoma (ccRCC), the most common histologic subtype of RCCs, demonstrates a wide spectrum of morphologic features (i.e., low-grade spindle cell, syncytial giant cells, and mucin-producing cells). However, papillary growth pattern in ccRCCs is rather a rare finding, which can present challenges in differential diagnostic work up. The aim of this study was to investigate ccRCCs with predominant papillary features from morphologic, immunohistochemical and molecular genetic perspectives. 23 clear cell renal cell carcinomas with papillary architecture were selected. Tumors were evaluated morphologically , immunohistochemically, and molecularly by next-generation sequencing (NGS). The diagnosis of MiT family translocation RCC was excluded by TFE3 immunohistochemistry. Mean age of patients was 65.2 years (range 42-81 years), and 19/23 were male. Tumor size ranged from 1.6 to 12.8 cm (median 6.5 cm). At a median follow-up of 2.5 years (range 1.5-9 years), 2 patients (8.7%) died of disease, 2 developed metastasis. Areas of papillary pattern accounted for approximately 40-100% of the tumor. CK7 was negative in non-papillary areas in majority of cases (20/23, 87%), and was only focally positive in 3/23 cases (13%). In papillary areas, AMACR was positive/focally positive in 17/23 (73.9%) cases and in the non-papillary areas it was positive/focally positive in 22/23 (95.6%) cases. CAIX was mainly negative in both non-papillary and papillary areas (15/23 [65%] and 16/23 [69.5%], respectively). Molecular analysis of 15 ana-lyzable cases revealed the most frequently mutated gene to be VHL (in 9 cases), followed by PRBM1 (in 2 cases) and 29 other different mutations in various genes. Papillary growth pattern in ccRCC is not an uncommon situation. Papillary RCC with clear cells and MiT family (TFE3) translocation RCCs are the major differential diagnostic considerations in such scenarios. Our NGS molecular analysis supported classifying such tumors as a morphologic variant of ccRCC.

Histopathology

Current available data on cytokeratin 7 immunostaining pattern in the clear cell renal cell carci... more Current available data on cytokeratin 7 immunostaining pattern in the clear cell renal cell carcinoma (RCC) spectrum is conflicting. The aim of this study was to assess CK7 immunoreactivity within the spectrum of clear cell renal neoplasms, including clear cell RCC, multicystic renal neoplasm of low malignant potential, and clear cell papillary RCC-like tumors. We analyzed two clones of CK7 and two tumor blocks for a total of 75 cases divided into five distinct groups: 1) low grade clear cell RCC, 2) high grade clear cell RCC, 3) multicystic renal neoplasm of low malignant potential, 4) clear cell RCC with cystic changes and 5) clear cell papillary RCC-like tumors. We found the highest CK7 reactivity in low grade clear cell RCC, multicystic renal neoplasm and clear cell papillary RCC-like groups, ranging from 60-93%. Our findings show that CK7 immunoreactivity in clear cell RCC is variable and the extent of staining depends on the grade and architectural growth patterns of the tumors. This article is protected by copyright. All rights reserved.

The American journal of surgical pathology, 2018

Three cases of superficial acral fibroblastic spindle cell neoplasms with EWSR1-SMAD3 fusion have... more Three cases of superficial acral fibroblastic spindle cell neoplasms with EWSR1-SMAD3 fusion have been recently reported. Their differential diagnosis is broad, primarily comprising rare tumors from the fibroblastic/myofibroblastic category. The aim of this report is to present 4 new cases of this entity and to discuss the appropriate differential diagnosis. Also, as the ERG antibody seems to be a characteristic marker for these tumors, we analyzed ERG immunostaining characteristics in potential mimics of this entity. All cases in our cohort occurred in women aged 5 to 68 years (mean, 36.5 y). Two were located on the hand, 1 on foot, and the last case arose on the calf. The tumor size ranged from 1 to 1.5 cm in the greatest dimension, with a mean size of 1.2 cm. Except for one recent case, follow-up was available, ranging from 7 to 18 years (mean, 11.7 y), with a recurrence noted in 1 case after 10 years. All tumors were subcutaneous and showed 2 main components. One consisted of bl...

The American Journal of Surgical Pathology

The term "idiopathic calcifying tenosynovitis" ... more The term "idiopathic calcifying tenosynovitis" (ICT) refers to a clinically and radiologically defined syndrome of pain and tendinous calcifications, most often involving the shoulder joint. A distinctive subset of ICT cases, termed "tenosynovitis with psammomatous calcifications" (TPC), occurs in the distal extremities and shows characteristic morphology, in particular psammomatous calcifications. As only 14 cases have been reported to date, TPC remains poorly recognized by both pathologists and clinicians. Twenty-three well-characterized cases of TPC along with all available radiologic and clinical information, including follow-up, were collected. Cases occurred in 21 females and 1 male (1 patient of unknown sex), aged 16 to 75 years (mean: 41), and almost exclusively involved the fingers and toes, except for one case in the elbow and one in the knee joint. The lesions ranged from 2 to 30 mm in size (mean: 10 mm). Pain was the most common presenting symptom (12/16 patients). A history of trauma or repetitive activity was present in 6 of 15 patients. None of the individuals was known to have disorders in calcium or phosphate metabolism. Radiographic studies showed a nonspecific, calcified mass. Typical morphologic features of TPC were invariably present, with degenerating tendinous tissue containing psammomatous calcifications, surrounded by a variably cellular, CD68/CD163/CD4-positive histiocyte-rich granulomatous host reaction. HUMARA assay in one case showed a polyclonal pattern. Clinical follow-up (19 patients; mean: 5.2 y; range: 1 to 14 y) showed no local recurrences. In this, the largest study of TPC to date, we confirm striking predilection of this distinctive pseudoneoplasm for the fingers and toes of young to middle-aged women. TPC should be rigorously distinguished from other forms of ICT, which typically involve large, proximal joints, and show simply dystrophic calcification involving tendinous tissues, and from tumoral calcinosis, which also involves large joints and often is associated with calcium and/or phosphate abnormalities. TPC appears to be related to trauma and/or repetitive activity and is cured with simple excision.

Human pathology, Jan 22, 2017

The presence and frequency of lipoblasts (LPB) in spindle cell lipomas (SCL) and pleomorphic lipo... more The presence and frequency of lipoblasts (LPB) in spindle cell lipomas (SCL) and pleomorphic lipomas (PL) has never been studied in detail on histologically, immunohistochemically and molecular genetically validated set of tumors. The authors investigated this feature by reviewing 91 cases of SCL and 38 PL. When more than three unequivocal LPB were found, the case was regarded as positive for the presence of LPB. All positive cases were then stained with CD34 and Retinoblastoma (Rb) protein antibodies and tested by FISH for MDM2 and CDK4 amplifications and the FUS gene rearrangements. The patients with SCL and PL containing LPB were 14 women and 47 men, the rest was of unknown gender. The cases usually presented as superficial, well-circumscribed soft tissue masses and most commonly occurred in the upper back and neck. CD34 was expressed in all cases, while Rb protein was consistently absent in all. Molecular genetic results, when available, were in concordance with the morphologica...

Virchows Archiv : an international journal of pathology, Jan 20, 2017

There is a group of lesions in the head and neck region derived from branchial arches and related... more There is a group of lesions in the head and neck region derived from branchial arches and related structures which, when inflamed, are characterized by the formation of cysts lined by squamous or glandular epithelium and surrounded by a heavy inflammatory infiltrate rich in germinal centers. In the thyroid, the main source of various structures which may cause diagnostic dilemma is the ultimobranchial body. To investigate the spectrum of such thyroid lesions, the consultation files were reviewed for thyroid samples containing pathological structures regarded to arise from the ultimobranchial body. Positive reaction with antibodies against CK5/6, p63, galectin 3, and CEA, and negative reaction with antibodies against thyroglobulin, TTF-1, and calcitonin were used to confirm the diagnosis. The specific subtype of the ultimobranchial body-derived lesion was then determined based on histological examination of H&E-stained slides. Twenty-one cases of ultimobranchial body-derived lesions ...

Annals of Diagnostic Pathology, 2017

Differentiated squamous intraepithelial lesion (dSIL) is morphologically and immunohistochemicall... more Differentiated squamous intraepithelial lesion (dSIL) is morphologically and immunohistochemically analogous in the whole anogenital region. dSIL is a premalignant lesion frequently misinterpreted histopathologically as a benign dermatosis. The authors describe a peculiar change in the basal cell layer of the epidermis/epithelium overlying anogenital melanocytic nevi that may histopathologically imitate dSIL. The aim of this study is to familiarize the pathologists with this pitfall to avoid its possible overdiagnosis as dysplasia. Further, we tried to explore the biological characteristics of the dSIL-like changes and to focus on the differential diagnostic aspects. Seventy cases of anogenital nevi were retrieved from our registry. All cases were stained with hematoxylin and eosin (H&E) and reviewed. Cases in which the epidermis overlying nevi featured atypical appearing basal keratinocytes in otherwise fully differentiated epithelium, variable degrees of acanthosis and parakeratosis were selected for additional investigation. Thirty cases meeting the above described criteria were identified. The patients were 8 males and 22 females, with age at the time of diagnosis ranging from 4 to 68years. Follow-up data were available for 28 patients (range 0.5-19years, mean 5.1), and to date, no signs of epithelial malignancy have been recorded. Immunohistochemically (IHC), the epidermis overlying nevi showed insignificant positivity for p53 in all tested cases. Melanocytic markers (S-100 protein, SOX10, Melan A) and cytokeratin AE1/3 labeled melanocytes and keratinocytes, respectively, enabling their distinction, especially in nevi featuring a junctional component. Differentiated squamous intraepithelial lesion-like changes seem to occur relatively often in the epidermis overlying anogenital melanocytic nevi. Since morphologically they are virtually identical to the "true" dSIL, their distinction largely depends on p53 expression in basal keratinocytes with normal p53 expression in dSIL-like changes and diffuse nuclear/p53-null immunostaining in the "true" dSIL serving as an essential differential diagnostic tool. dSIL-like alterations seem to have no malignant potential, as to date, none of the patients included in this study have shown any signs of epithelial malignancy.

Annals of Diagnostic Pathology, 2017

The authors present a distinctive perineurioma (PN) variant which morphologically strongly resemb... more The authors present a distinctive perineurioma (PN) variant which morphologically strongly resembles monophasic fibrous synovial sarcoma (MSS). The patients were 3 males and 1 female. The age ranged from 15 to 61years (mean: 44years). Locations included the sole, lower jaw, palm and foot. The tumor size ranged from 1.3cm to 2.5cm in the largest dimension (mean 1.8cm). Morphologically, all tumors had an identical, monotonous appearance. The perineurial cells were closely packed and created a confluent cellular whorls and/or sheets in a scarce stroma, with only focally discernible long, slender cytoplasmic processes typical for perineurial differentiation. The nuclei were rounded or slightly elongated to tapered, without nuclear atypia. Mitoses were rare to completely absent. Atypical mitoses, hemorrhage, necrosis or calcifications were not present. The proliferative index (Ki-67) was 1-3%. All analyzed tumors were positive for EMA, Claudin-1, GLUT-1 and negative with S100 protein, CD34, OSCAR, CK7 and TLE-1. Two cases were tested by fluorescence in situ hybridization and neither showed alterations of the SYT gene. One case studied by electron microscopy showed characteristic features of perineurial differentiation. Follow-up was available for two patients both of which showed no evidence of disease at 8years and 6months, respectively. Based on their bland morphology, perineurial features and presumably benign clinical outcome we propose the term "whorling cellular perineurioma" for these tumors, which may represent an extremely cellular variant of sclerosing PN. Awareness of this PN subtype and its distinction from MSS is of utmost clinical significance.

Human Pathology, 2016

The authors present 11 cases of plexiform neurofibroma (PN) that featured a very characteristic t... more The authors present 11 cases of plexiform neurofibroma (PN) that featured a very characteristic type of cell appearing as multivacuolated mucin-filled cells (MMFC). The 11 cases were obtained after reviewing 109 cases of PN. Six out of 10 patients showed clinical features of neurofibromatosis type 1. The size of PN ranged from 0.8 cm to 11.5 cm in the largest dimension. The lesions represented classical PN in all cases with myxoid, hypocellular stroma. The MMFC were found within the most myxoid tumorous nodules and were haphazardly located, typically featuring a variably sized, multivacuolated cytoplasm divided by fine septa with a small polygonal nucleus on one side, which was often compressed or slightly indented by the cytoplasmic mucous substances. In many cases, the cells resembled a soccer ball or a jellyfish. In all tested cases (n = 9), the MMFC stained for CD34; six cases were also positive with GLUT-1 antibody, and two cases expressed Claudin-1, whereas S-100 protein was negative. For comparison, we have reviewed a series of randomly selected non-PN, malignant peripheral nerve sheath tumors (MPNST) and of cases featuring non-neoplastic nerve trunks in our files, in which no MMFC were encountered. MMFC seem to be unique to myxoid areas of PN, where they occur in about 10% of cases. Their exact histogenesis is unclear but they might represent an intermediate type of cell between perineurial cells and fibroblasts. The awareness of this cell type in PN is especially important in limited (small) biopsy specimens where their recognition may provide a clue for the correct diagnosis.

a r t i c l e i n f o Available online xxxx Oncocytic papillary renal cell carcinoma (PRCC) is a ... more a r t i c l e i n f o Available online xxxx Oncocytic papillary renal cell carcinoma (PRCC) is a distinct subtype of PRCC, listed as a possible new variant of PRCC in the 2016 WHO classification. It is composed of papillae aligned by large single-layered eosinophilic cells showing linearly arranged oncocytoma-like nuclei. We analyzed clinicopathologic, morphologic, immunohistochemical and molecular-genetic characteristics of 11 oncocytic PRCCs with prominent tumor lymphocytic infiltrate, morphologically resembling Warthin's tumor. The patients were predominantly males (8/11, 73%), with an average age of 59 years (range 14–76), and a mean tumor size of 7 cm (range 1–22 cm). Tumors had the features of oncocytic PRCCs with focal pseudostratification in 8/11 cases and showed dense stromal inflammatory infiltration in all cases. Papillary growth pattern was predominant, comprising more than 60% of tumor volume. Tubular and solid components were present in 5 and 3 cases, respectively. Uniform immunohistochemical positivity was found for AMACR, PAX-8, MIA, vimentin, and OSCAR. Tumors were mostly negative for carboanhydrase 9, CD117, CK20, and TTF-1. Immu-nohistochemical stains for DNA mismatch repair proteins MLH1 and PMS2 were retained in all cases, while MSH2 and MSH6 were negative in 1 case. Tumor infiltrating lymphocytes (TILs) consisted of both B and T cells. Chromosomal copy number variation analysis showed great variability in 5 cases, ranging from a loss of one single chromosome to complex genome rearrangements. Only one case showed gains of chromosomes 7 and 17, among other aberrations. In 4 cases no numerical imbalance was found. Follow up data was available for 9 patients (median 47.6 months, range 1–132). In 6 patients no lethal progression was noted, while 3 died of disease. In conclusion, Warthin-like PRCC is morphologically very close to oncocytic PRCC, from which it differs by the presence of dense lymphoid stroma. Chromosomal numerical aberration pattern of these tumors is variable; only one case showed gains of chromosomes 7 and 17. Warthin-like PRCC is a potentially aggressive tumor since a lethal outcome was recorded in 3/9 cases.

We present a series of 16 salivary gland tumors with histomorphologic and immunohistochemical fea... more We present a series of 16 salivary gland tumors with histomorphologic and immunohistochemical features reminiscent of secretory carcinoma of the breast. This is a hitherto undescribed and distinctive salivary gland neoplasm, with features resembling both salivary acinic cell carcinoma (AciCC) and lowgrade cystadenocarcinoma, and displaying strong similarities to breast secretory carcinoma. Microscopically, the tumors have a lobulated growth pattern and are composed of microcystic and glandular spaces with abundant eosinophilic homogenous or bubbly secretory material positive for periodic acid-Schiff, mucicarmine, MUC1, MUC4, and mammaglobin. The neoplasms also show strong vimentin, S-100 protein, and STAT5a positivity. For this tumor, we propose a designation mammary analogue secretory carcinoma of salivary glands (MASC). The 16 patients comprised 9 men and 7 women, with a mean age of 46 years (range 21 to 75). Thirteen cases occurred in the parotid gland, and one each in the minor salivary glands of the buccal mucosa, upper lip, and palate. The mean size of the tumors was 2.1 cm (range 0.7 to 5.5 cm). The duration of symptoms was recorded in 11 cases and ranged from 2 months to 30 years. Clinical follow-up was available in 13 cases, and ranged from 3 months to 10 years. Four patients suffered local recurrences. Two patients died, 1 of them owing to multiple local recurrences with extension to the temporal bone, and another owing to metastatic dissemination to cervical lymph nodes, pleura, pericardium, and lungs. We have shown a t(12;15) (p13;q25) ETV6-NTRK3 translocation in all but one case of MASC suitable for analysis. One case was not analyzable and another was not available for testing. This translocation was not found in any conventional salivary AciCC (12 cases), nor in other tumor types including pleomorphic adenoma (1 case) and low-grade cribriform cystadenocarcinoma (1 case), whereas ETV6-NTRK3 gene rearrangements were proven in all 3 tested cases of mammary secretory carcinoma. Thus, our results strongly support the concept that MASC and AciCC are different entities.

Laboratory Investigation

Results: Strictures were characterized by a mean 2.3-fold increase in overall mural thickness and... more Results: Strictures were characterized by a mean 2.3-fold increase in overall mural thickness and by 2.6and 1.8-fold increases in the areas occupied by smooth muscle and collagen, respectively. Approximately half the increase in wall thickness was attributable to a mean 22-fold expansion of the muscularis mucosae (MM) from 2.2±1.6% to 16.5±10.1% of the total mural thickness and the remainder of the increase to expansions of the internal layer of muscularis propria (MP-I) and submucosa (SM). The external layer of the muscularis propria was similar in thickness and composition to controls. Microscopically, the expanded MM featured (1) architectural disarray, (2) myocyte hyperplasia and (3) pericellular collagen fibers. In contrast, the thickened MP-I featured (1) preserved muscular architecture, (2) no pericellular collagen fibers, and (3) widened intramuscular septa with increased collagen. The SM exhibited fibrosis in continuity with the intramuscular septa. Additionally, submucosal arteries and veins frequently exhibited eccentric fibromuscular hyperplasia which was polarized toward the mucosa. Conclusions: Stricturing Crohn’s ileitis is characterized by distinctive fibromuscular alterations in the individual intestinal wall layers. These alterations may reflect differential mesenchymal responses to luminal-based and transmural inflammatory stimuli. The implications for stricture pathogenesis may help guide progress toward prevention and therapy.

Annals of Diagnostic Pathology

Clear cell renal cell carcinoma (ccRCC), the most common histologic subtype of RCCs, demonstrates... more Clear cell renal cell carcinoma (ccRCC), the most common histologic subtype of RCCs, demonstrates a wide spectrum of morphologic features (i.e., low-grade spindle cell, syncytial giant cells, and mucin-producing cells). However, papillary growth pattern in ccRCCs is rather a rare finding, which can present challenges in differential diagnostic work up. The aim of this study was to investigate ccRCCs with predominant papillary features from morphologic, immunohistochemical and molecular genetic perspectives. 23 clear cell renal cell carcinomas with papillary architecture were selected. Tumors were evaluated morphologically , immunohistochemically, and molecularly by next-generation sequencing (NGS). The diagnosis of MiT family translocation RCC was excluded by TFE3 immunohistochemistry. Mean age of patients was 65.2 years (range 42-81 years), and 19/23 were male. Tumor size ranged from 1.6 to 12.8 cm (median 6.5 cm). At a median follow-up of 2.5 years (range 1.5-9 years), 2 patients (8.7%) died of disease, 2 developed metastasis. Areas of papillary pattern accounted for approximately 40-100% of the tumor. CK7 was negative in non-papillary areas in majority of cases (20/23, 87%), and was only focally positive in 3/23 cases (13%). In papillary areas, AMACR was positive/focally positive in 17/23 (73.9%) cases and in the non-papillary areas it was positive/focally positive in 22/23 (95.6%) cases. CAIX was mainly negative in both non-papillary and papillary areas (15/23 [65%] and 16/23 [69.5%], respectively). Molecular analysis of 15 ana-lyzable cases revealed the most frequently mutated gene to be VHL (in 9 cases), followed by PRBM1 (in 2 cases) and 29 other different mutations in various genes. Papillary growth pattern in ccRCC is not an uncommon situation. Papillary RCC with clear cells and MiT family (TFE3) translocation RCCs are the major differential diagnostic considerations in such scenarios. Our NGS molecular analysis supported classifying such tumors as a morphologic variant of ccRCC.

Histopathology

Current available data on cytokeratin 7 immunostaining pattern in the clear cell renal cell carci... more Current available data on cytokeratin 7 immunostaining pattern in the clear cell renal cell carcinoma (RCC) spectrum is conflicting. The aim of this study was to assess CK7 immunoreactivity within the spectrum of clear cell renal neoplasms, including clear cell RCC, multicystic renal neoplasm of low malignant potential, and clear cell papillary RCC-like tumors. We analyzed two clones of CK7 and two tumor blocks for a total of 75 cases divided into five distinct groups: 1) low grade clear cell RCC, 2) high grade clear cell RCC, 3) multicystic renal neoplasm of low malignant potential, 4) clear cell RCC with cystic changes and 5) clear cell papillary RCC-like tumors. We found the highest CK7 reactivity in low grade clear cell RCC, multicystic renal neoplasm and clear cell papillary RCC-like groups, ranging from 60-93%. Our findings show that CK7 immunoreactivity in clear cell RCC is variable and the extent of staining depends on the grade and architectural growth patterns of the tumors. This article is protected by copyright. All rights reserved.

The American journal of surgical pathology, 2018

Three cases of superficial acral fibroblastic spindle cell neoplasms with EWSR1-SMAD3 fusion have... more Three cases of superficial acral fibroblastic spindle cell neoplasms with EWSR1-SMAD3 fusion have been recently reported. Their differential diagnosis is broad, primarily comprising rare tumors from the fibroblastic/myofibroblastic category. The aim of this report is to present 4 new cases of this entity and to discuss the appropriate differential diagnosis. Also, as the ERG antibody seems to be a characteristic marker for these tumors, we analyzed ERG immunostaining characteristics in potential mimics of this entity. All cases in our cohort occurred in women aged 5 to 68 years (mean, 36.5 y). Two were located on the hand, 1 on foot, and the last case arose on the calf. The tumor size ranged from 1 to 1.5 cm in the greatest dimension, with a mean size of 1.2 cm. Except for one recent case, follow-up was available, ranging from 7 to 18 years (mean, 11.7 y), with a recurrence noted in 1 case after 10 years. All tumors were subcutaneous and showed 2 main components. One consisted of bl...

The American Journal of Surgical Pathology

The term "idiopathic calcifying tenosynovitis" ... more The term "idiopathic calcifying tenosynovitis" (ICT) refers to a clinically and radiologically defined syndrome of pain and tendinous calcifications, most often involving the shoulder joint. A distinctive subset of ICT cases, termed "tenosynovitis with psammomatous calcifications" (TPC), occurs in the distal extremities and shows characteristic morphology, in particular psammomatous calcifications. As only 14 cases have been reported to date, TPC remains poorly recognized by both pathologists and clinicians. Twenty-three well-characterized cases of TPC along with all available radiologic and clinical information, including follow-up, were collected. Cases occurred in 21 females and 1 male (1 patient of unknown sex), aged 16 to 75 years (mean: 41), and almost exclusively involved the fingers and toes, except for one case in the elbow and one in the knee joint. The lesions ranged from 2 to 30 mm in size (mean: 10 mm). Pain was the most common presenting symptom (12/16 patients). A history of trauma or repetitive activity was present in 6 of 15 patients. None of the individuals was known to have disorders in calcium or phosphate metabolism. Radiographic studies showed a nonspecific, calcified mass. Typical morphologic features of TPC were invariably present, with degenerating tendinous tissue containing psammomatous calcifications, surrounded by a variably cellular, CD68/CD163/CD4-positive histiocyte-rich granulomatous host reaction. HUMARA assay in one case showed a polyclonal pattern. Clinical follow-up (19 patients; mean: 5.2 y; range: 1 to 14 y) showed no local recurrences. In this, the largest study of TPC to date, we confirm striking predilection of this distinctive pseudoneoplasm for the fingers and toes of young to middle-aged women. TPC should be rigorously distinguished from other forms of ICT, which typically involve large, proximal joints, and show simply dystrophic calcification involving tendinous tissues, and from tumoral calcinosis, which also involves large joints and often is associated with calcium and/or phosphate abnormalities. TPC appears to be related to trauma and/or repetitive activity and is cured with simple excision.

Human pathology, Jan 22, 2017

The presence and frequency of lipoblasts (LPB) in spindle cell lipomas (SCL) and pleomorphic lipo... more The presence and frequency of lipoblasts (LPB) in spindle cell lipomas (SCL) and pleomorphic lipomas (PL) has never been studied in detail on histologically, immunohistochemically and molecular genetically validated set of tumors. The authors investigated this feature by reviewing 91 cases of SCL and 38 PL. When more than three unequivocal LPB were found, the case was regarded as positive for the presence of LPB. All positive cases were then stained with CD34 and Retinoblastoma (Rb) protein antibodies and tested by FISH for MDM2 and CDK4 amplifications and the FUS gene rearrangements. The patients with SCL and PL containing LPB were 14 women and 47 men, the rest was of unknown gender. The cases usually presented as superficial, well-circumscribed soft tissue masses and most commonly occurred in the upper back and neck. CD34 was expressed in all cases, while Rb protein was consistently absent in all. Molecular genetic results, when available, were in concordance with the morphologica...

Virchows Archiv : an international journal of pathology, Jan 20, 2017

There is a group of lesions in the head and neck region derived from branchial arches and related... more There is a group of lesions in the head and neck region derived from branchial arches and related structures which, when inflamed, are characterized by the formation of cysts lined by squamous or glandular epithelium and surrounded by a heavy inflammatory infiltrate rich in germinal centers. In the thyroid, the main source of various structures which may cause diagnostic dilemma is the ultimobranchial body. To investigate the spectrum of such thyroid lesions, the consultation files were reviewed for thyroid samples containing pathological structures regarded to arise from the ultimobranchial body. Positive reaction with antibodies against CK5/6, p63, galectin 3, and CEA, and negative reaction with antibodies against thyroglobulin, TTF-1, and calcitonin were used to confirm the diagnosis. The specific subtype of the ultimobranchial body-derived lesion was then determined based on histological examination of H&E-stained slides. Twenty-one cases of ultimobranchial body-derived lesions ...

Annals of Diagnostic Pathology, 2017

Differentiated squamous intraepithelial lesion (dSIL) is morphologically and immunohistochemicall... more Differentiated squamous intraepithelial lesion (dSIL) is morphologically and immunohistochemically analogous in the whole anogenital region. dSIL is a premalignant lesion frequently misinterpreted histopathologically as a benign dermatosis. The authors describe a peculiar change in the basal cell layer of the epidermis/epithelium overlying anogenital melanocytic nevi that may histopathologically imitate dSIL. The aim of this study is to familiarize the pathologists with this pitfall to avoid its possible overdiagnosis as dysplasia. Further, we tried to explore the biological characteristics of the dSIL-like changes and to focus on the differential diagnostic aspects. Seventy cases of anogenital nevi were retrieved from our registry. All cases were stained with hematoxylin and eosin (H&E) and reviewed. Cases in which the epidermis overlying nevi featured atypical appearing basal keratinocytes in otherwise fully differentiated epithelium, variable degrees of acanthosis and parakeratosis were selected for additional investigation. Thirty cases meeting the above described criteria were identified. The patients were 8 males and 22 females, with age at the time of diagnosis ranging from 4 to 68years. Follow-up data were available for 28 patients (range 0.5-19years, mean 5.1), and to date, no signs of epithelial malignancy have been recorded. Immunohistochemically (IHC), the epidermis overlying nevi showed insignificant positivity for p53 in all tested cases. Melanocytic markers (S-100 protein, SOX10, Melan A) and cytokeratin AE1/3 labeled melanocytes and keratinocytes, respectively, enabling their distinction, especially in nevi featuring a junctional component. Differentiated squamous intraepithelial lesion-like changes seem to occur relatively often in the epidermis overlying anogenital melanocytic nevi. Since morphologically they are virtually identical to the "true" dSIL, their distinction largely depends on p53 expression in basal keratinocytes with normal p53 expression in dSIL-like changes and diffuse nuclear/p53-null immunostaining in the "true" dSIL serving as an essential differential diagnostic tool. dSIL-like alterations seem to have no malignant potential, as to date, none of the patients included in this study have shown any signs of epithelial malignancy.

Annals of Diagnostic Pathology, 2017

The authors present a distinctive perineurioma (PN) variant which morphologically strongly resemb... more The authors present a distinctive perineurioma (PN) variant which morphologically strongly resembles monophasic fibrous synovial sarcoma (MSS). The patients were 3 males and 1 female. The age ranged from 15 to 61years (mean: 44years). Locations included the sole, lower jaw, palm and foot. The tumor size ranged from 1.3cm to 2.5cm in the largest dimension (mean 1.8cm). Morphologically, all tumors had an identical, monotonous appearance. The perineurial cells were closely packed and created a confluent cellular whorls and/or sheets in a scarce stroma, with only focally discernible long, slender cytoplasmic processes typical for perineurial differentiation. The nuclei were rounded or slightly elongated to tapered, without nuclear atypia. Mitoses were rare to completely absent. Atypical mitoses, hemorrhage, necrosis or calcifications were not present. The proliferative index (Ki-67) was 1-3%. All analyzed tumors were positive for EMA, Claudin-1, GLUT-1 and negative with S100 protein, CD34, OSCAR, CK7 and TLE-1. Two cases were tested by fluorescence in situ hybridization and neither showed alterations of the SYT gene. One case studied by electron microscopy showed characteristic features of perineurial differentiation. Follow-up was available for two patients both of which showed no evidence of disease at 8years and 6months, respectively. Based on their bland morphology, perineurial features and presumably benign clinical outcome we propose the term "whorling cellular perineurioma" for these tumors, which may represent an extremely cellular variant of sclerosing PN. Awareness of this PN subtype and its distinction from MSS is of utmost clinical significance.

Human Pathology, 2016

The authors present 11 cases of plexiform neurofibroma (PN) that featured a very characteristic t... more The authors present 11 cases of plexiform neurofibroma (PN) that featured a very characteristic type of cell appearing as multivacuolated mucin-filled cells (MMFC). The 11 cases were obtained after reviewing 109 cases of PN. Six out of 10 patients showed clinical features of neurofibromatosis type 1. The size of PN ranged from 0.8 cm to 11.5 cm in the largest dimension. The lesions represented classical PN in all cases with myxoid, hypocellular stroma. The MMFC were found within the most myxoid tumorous nodules and were haphazardly located, typically featuring a variably sized, multivacuolated cytoplasm divided by fine septa with a small polygonal nucleus on one side, which was often compressed or slightly indented by the cytoplasmic mucous substances. In many cases, the cells resembled a soccer ball or a jellyfish. In all tested cases (n = 9), the MMFC stained for CD34; six cases were also positive with GLUT-1 antibody, and two cases expressed Claudin-1, whereas S-100 protein was negative. For comparison, we have reviewed a series of randomly selected non-PN, malignant peripheral nerve sheath tumors (MPNST) and of cases featuring non-neoplastic nerve trunks in our files, in which no MMFC were encountered. MMFC seem to be unique to myxoid areas of PN, where they occur in about 10% of cases. Their exact histogenesis is unclear but they might represent an intermediate type of cell between perineurial cells and fibroblasts. The awareness of this cell type in PN is especially important in limited (small) biopsy specimens where their recognition may provide a clue for the correct diagnosis.

a r t i c l e i n f o Available online xxxx Oncocytic papillary renal cell carcinoma (PRCC) is a ... more a r t i c l e i n f o Available online xxxx Oncocytic papillary renal cell carcinoma (PRCC) is a distinct subtype of PRCC, listed as a possible new variant of PRCC in the 2016 WHO classification. It is composed of papillae aligned by large single-layered eosinophilic cells showing linearly arranged oncocytoma-like nuclei. We analyzed clinicopathologic, morphologic, immunohistochemical and molecular-genetic characteristics of 11 oncocytic PRCCs with prominent tumor lymphocytic infiltrate, morphologically resembling Warthin's tumor. The patients were predominantly males (8/11, 73%), with an average age of 59 years (range 14–76), and a mean tumor size of 7 cm (range 1–22 cm). Tumors had the features of oncocytic PRCCs with focal pseudostratification in 8/11 cases and showed dense stromal inflammatory infiltration in all cases. Papillary growth pattern was predominant, comprising more than 60% of tumor volume. Tubular and solid components were present in 5 and 3 cases, respectively. Uniform immunohistochemical positivity was found for AMACR, PAX-8, MIA, vimentin, and OSCAR. Tumors were mostly negative for carboanhydrase 9, CD117, CK20, and TTF-1. Immu-nohistochemical stains for DNA mismatch repair proteins MLH1 and PMS2 were retained in all cases, while MSH2 and MSH6 were negative in 1 case. Tumor infiltrating lymphocytes (TILs) consisted of both B and T cells. Chromosomal copy number variation analysis showed great variability in 5 cases, ranging from a loss of one single chromosome to complex genome rearrangements. Only one case showed gains of chromosomes 7 and 17, among other aberrations. In 4 cases no numerical imbalance was found. Follow up data was available for 9 patients (median 47.6 months, range 1–132). In 6 patients no lethal progression was noted, while 3 died of disease. In conclusion, Warthin-like PRCC is morphologically very close to oncocytic PRCC, from which it differs by the presence of dense lymphoid stroma. Chromosomal numerical aberration pattern of these tumors is variable; only one case showed gains of chromosomes 7 and 17. Warthin-like PRCC is a potentially aggressive tumor since a lethal outcome was recorded in 3/9 cases.