Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID).

PURPOSE: A subset of patients with common variable immunodeficiency (CVID) develops granulomatous and lymphocytic interstitial lung disease (GLILD), a restrictive lung disease associated with early mortality. The optimal therapy for GLILD is unknown. This study was undertaken to see if rituximab and azathioprine (combination chemotherapy) would improve pulmonary function and/or radiographic abnormalities in patients with CVID and GLILD. METHODS: A retrospective chart review of patients with CVID and GLILD who were treated with combination chemotherapy was performed. Complete pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) scans of the chest were done prior to therapy and >6 months later. HRCT scans of the chest were blinded, randomized, and scored independently (in pairs) by two radiologists. The differences between pre- and post-treatment HRCT scores and PFT parameters were analyzed. RESULTS: Seven patients with CVID and GLILD met inclusion criteria. Post-treatment increases were noted in both FEV1 (p=0.034) and FVC (p=0.043). HRCT scans of the chest demonstrated improvement in total score (p=0.018), pulmonary consolidations (p=0.041), ground-glass opacities (p=0.020) nodular opacities (p=0.024), and both the presence and extent of bronchial wall thickening (p=0.014, 0.026 respectively). No significant chemotherapy-related complications occurred. CONCLUSIONS: Combination chemotherapy improved pulmonary function and decreased radiographic abnormalities in patients with CVID and GLILD.

Smoking-related interstitial lung disease.

Pulmonary diseases associated with tobacco smoking are a complex group of disorders ranging from chronic obstructive pulmonary disease (COPD) to lung cancer. Interstitial lung diseases (ILDs) have only recently been linked to smoking. The ILDs related to smoking include respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, and pulmonary Langerhans cell histiocytosis. The relationship of smoking with each of these entities has been largely established on the weight of epidemiologic evidence. Although they have been retained as distinct and separate conditions in various classifications of interstitial lung diseases, these 3 entities share a number of clinical, radiologic, and pathologic features suggesting that they represent a spectrum of patterns of interstitial lung disease occurring in predisposed individuals who smoke. Evaluation of histologic features, particularly in surgical lung biopsy samples, is important in making the distinction between these disorders. However, even after tissue biopsy, it may sometimes be difficult to clearly separate these entities. The importance of making the distinction between them lies in the different clinical management strategies used. Further experimental evidence, including genetic information, may be important in improving our understanding of these diseases.

Tissue Harvester with Functional Valve (THFV): Shidham's device for reproducibly higher specimen yield by fine needle aspiration biopsy with easy to perform steps.

BACKGROUND: Fine needle aspiration biopsy (FNAB) cytology has been a highly effective methodology for tissue diagnosis and for various ancillary studies including molecular tests. In addition to other benefits, FNAB predominantly retrieves the diagnostic loosely cohesive cells in the lesion as compared to the adjacent supporting stroma with relatively higher cohesiveness. However, FNAB procedure performed with currently available resources is highly skill dependent with inter-performer variability, which compromises its full potential as a diagnostic tool. In this study we report a device overcoming these limitations. METHODS: 'Tissue Harvester with Functional Valve' (THFV) was evaluated as part of a phase 1 National Institute of Health (NIH) research grant under Small Business Technology Transfer (STTR) Program. Working prototypes of the device were prepared. Each of the four cytopathologists with previous cytopathology fellowship training and experience in performing FNAB evaluated 5 THFV and 5 hypodermic needles resulting in 40 specimens (20 with THFV, 20 with hypodermic needles). A piece of fresh cattle liver stuffed in latex glove was used as the specimen. Based on these results a finished design was finalized. RESULTS: The smears and cell blocks prepared from the specimens obtained by THFV were superior in terms of cellularity to specimens obtained with hypodermic needles. The tissuecrit of specimens obtained with THFV ranged from 70 to 100 microl (mean 87, SD 10), compared to 17 to 30 microl (mean 24, SD 4) with conventional hypodermic needles (p < .0001, Student t-test). The technical ease [on a scale of 1 (easy) to 5 (difficult)] with THFV ranged from 1 to 2 as compared to 2 to 3 with hypodermic needles. CONCLUSION: The specimen yield with the new THFV was significantly higher when compared to hypodermic needles. Also, the FNAB procedure with THFV was relatively easier in comparison with hypodermic needles. The final version of Shidham's THFV device would improve the FNAB specimen yield by eliminating the skill factor. The increased specimen yield by this device would also facilitate wider application of FNAB specimens for various ancillary tests, including molecular tests.

Primary non-Hodgkin's lymphoma of breast: a case report.

Primary breast lymphoma is a relatively uncommon neoplasm, majority being of B-cell origin. Mucosa associated lymphoid tissue (MALT) is one of the common types of breast lymphomas. Though cytologic diagnosis of breast lymphoma is an easy procedure and provides guidance for appropriate pre-operative management, it is often impossible to differentiate a low grade lymphoma from reactive proliferation. A similar difficulty was encountered in the present case, a 42 year old female with a breast lump. Fine needle aspiration cytology revealed a mixed lymphoid cell population. Lymphoepithelial lesions were identified histologically, and the majority of the cell population were confirmed as lymphoma cells of B-cell origin on immunohistochemistry. This case highlights the limitations of cytology and the importance of histological examination supported by immunohistochemistry for making a diagnosis of low grade primary breast lymphoma.

Improved immunohistochemical evaluation of micrometastases in sentinel lymph nodes of cutaneous melanoma with 'MCW melanoma cocktail'--a mixture of monoclonal antibodies to MART-1, Melan-A, and tyrosinase.

BACKGROUND: MART-1, Melan-A, and Tyrosinase have shown encouraging results for evaluation of melanoma micrometastases in sentinel lymph nodes, as compared to conventionally used S-100 protein and HMB-45. To achieve higher sensitivity, some studies recommend evaluation of three sections, each at intervals of 200 micron. This would mean, routine staining of three adjacent sections in each of the three clusters at intervals of 200 micron, requiring nine slides resulting in added expense. If a cocktail of these antibodies could be used, only one section would be required instead of three generating significant cost savings. METHODS: We prepared a combination of monoclonal antibodies to these three immunomarkers in optimized dilutions (MART-1, clone M2-7C10, dilution 1:500; Melan-A, clone A103, dilution 1:100; and Tyrosinase, clone T311, dilution 1:50) and designated it as 'MCW melanoma cocktail'. Formalin-fixed paraffin-embedded tissue sections of sentinel lymph nodes from patients with cutaneous melanoma, without macro-metastases were evaluated with this cocktail. RESULTS: Melanoma micrometastases were easily detectable with the cocktail in 41 out of 188 slices (8/24 cases). The diagnostic accuracy amongst five pathologists did not show statistically significant difference. Out of 188 slices, 78 had adjacent sections immunostained individually with MART-1 and Melan-A during our previous study. Of these 78 slices, 21 were positive for melanoma micrometastases with MART-1 and Melan-A individually. However, the adjacent section of these slices immunostained with the cocktail detected metastases in four additional slices. Thus, MART-1 and Melan-A could not detect melanoma micrometastases individually in 16% (4/25) of slices positive with the cocktail. Benign capsular nevi were immunoreactive for the cocktail in 4.8% (9/188) slices. All 81 slices of negative test controls (sentinel lymph nodes of mammary carcinoma) were interpreted correctly as negative for melanoma micrometastases. CONCLUSIONS: The melanoma cocktail facilitated easy interpretation of melanoma micrometastases in sentinel lymph nodes with high interobserver agreement. There was improvement in detection rate with the cocktail as compared to MART-1 and Melan-A individually. Furthermore, this approach facilitates cost savings.

Intraoperative cytology increases the diagnostic accuracy of frozen sections for the confirmation of various tissues in the parathyroid region.

The identification of parathyroid gland tissue and its distinction from adjacent structures such as thyroid gland, lymphoid, fibroadipose, and, rarely, thymic tissues on frozen section (FS) may be challenging owing to freezing artifact. Intraoperative cytology (IC) provides valuable complementary morphologic details. We evaluated 72 specimens with IC alone (group 1), followed by interpretation with FS to reach a final interpretation using IC and FS together (group 2). An additional 105 specimens were evaluated by FS alone (group 3). Permanent section diagnosis was used as the "gold standard." Sensitivity and specificity were 100% for group 2, compared with lower values for group 1 (98% and 100%, respectively) and group 3 (94% and 94%, respectively). IC is a valuable adjunct to FS during intraoperative consultation for evaluation of tissue in a parathyroid location.

Mantle cell lymphoma in lymph nodes with metastatic small cell carcinoma of lung: a diagnostic and treatment dilemma.

We report a rare case of small cell carcinoma (SCC) of lung, metastatic to ipsilateral hilar and peribronchial lymph nodes with synchronous mantle cell lymphoma (MCL), in a 58-year-old female. She was treated with Cisplatin, Etoposide, and Rituximab, and remained in complete remission for approximately two and a half years following the initial diagnosis. To the best of our knowledge, synchronous SCC and MCL or SCC metastatic to lymph nodes involved by MCL has not been previously reported. In this case, the features of MCL were very inconspicuous in the lymph nodes with extensive metastases of SCC. The presence of MCL was confirmed by immunohistochemistry and fluorescence in situ hybridization (FISH). The co-existence of lymphoma and metastatic carcinoma in the same lymph node, as seen in this case, highlights the significance of analyzing subtle lymphoid architectural changes, and applying ancillary studies such as immunohistochemistry and molecular analysis in suspicious cases. The management of synchronous SCC and MCL requires consideration of their respective biologic behavior, and cumulative toxicity of treatment regimens of both tumors. In such cases an optimum treatment strategy should be adopted to cover both malignancies with minimal toxic effect.

Immunohistochemical comparison of gastrointestinal stromal tumor and solitary fibrous tumor.

CONTEXT: The differential diagnosis of gastrointestinal stromal tumors (GIST) and solitary fibrous tumors (SFT) may be a diagnostic challenging because of overlapping clinicopathologic features. Many studies have shown consistent immunoreactivity for CD117 (c-Kit) in GIST. However, only a few studies have evaluated CD117 expression in SFT, and these studies have used an antibody from Santa Cruz Biotechnology. In non-GIST lesions, reactivity with this antibody has been shown to differ from that with a CD117 antibody from Dako Corporation. The immunoreactivity of SFT with the Dako CD117 antibody has not been reported. Conversely, CD99 is a marker for SFT, and its expression in GIST has not been evaluated. OBJECTIVE: To study the immunohistochemical profiles of GIST and SFT to evaluate their diagnostic overlap. DESIGN: We studied the immunoreactivity of 27 unequivocal GIST and 19 unequivocal extra-abdominal SFT for CD117, CD34, CD99, alpha-smooth muscle actin, vimentin, CD31, S100 protein, and muscle-specific actin. All antibodies, including CD117, were from Dako Corporation. RESULTS: We found positive immunoreactivity for CD117 in 100% of GIST and none of SFT; for CD34 in 89% of GIST, and 100% of SFT; for CD99 in 89% of GIST and 100% of SFT; for alpha-smooth muscle actin in 48% of GIST and 31% of SFT; for vimentin in 89% of GIST and 90% of SFT; and for muscle-specific actin in 22% of GIST and none of SFT. None of the GIST or SFT showed immunoreactivity for CD31 and S100 protein. CONCLUSIONS: The major difference between GIST and SFT was strong CD117 immunoexpression in all GIST and an absence of this expression in all SFT. With the exception of muscle-specific actin, the prevalence of immunoreactivity for the markers studied did not differ substantially between these 2 tumors. We conclude that GIST and SFT show distinctly divergent immunoprofiles with respect to CD117 and muscle-specific actin.

Fatty metamorphosis and other patterns in fibrous dysplasia.

BACKGROUND: Interpretation of small biopsy fragments from suspected lesions of fibrous dysplasia with unusual clinical and/or radiological features may be challenging due to wide histomorphological spectrum of stromal appearances. Awareness of these variations should improve diagnostic confidence. METHODS: We retrospectively studied 26 cases of fibrous dysplasia (F- 19, M- 7; Ages ranged from 10 to 53 years) with confirmed diagnosis. The sites of the lesions were skull bones (9), humerus (1), femur (8), tibia (2), fibula (3), talus (1), mandible (1), and maxilla (1). RESULTS: Different stromal patterns, variably admixed with the classical pattern, were observed in 58%(15/26) of the cases. 20%(3/15) of these had more than one pattern. Focal fatty metamorphosis as groups of fat cells in the central portion of the lesion in the stroma of fibrous dysplasia between osseous trabeculae was observed in 23%(6/26) cases. Other patterns included myxoid stroma in 16%(4/26), collagenization of stroma in 12%(3/26), stroma rich pattern (with paucity of trabeculae) in 12%(3/26), foci of few foam cells in 23% (6/26), and calcified spherules in 12%(3/26). Focal osteoblastic rimming of trabeculae was observed only in 4%(1/26). CONCLUSIONS: Various stromal variations and previously unreported fatty metamorphosis were frequently observed in fibrous dysplasia.

Microglandular hyperplasia has a cytomorphological spectrum overlapping with atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (ASC-H).

We retrospectively evaluated cytological interpretations of conventional cervical smears in 48 cases of biopsy-proven microglandular hyperplasia and compared them with 15 negative controls. A glandular pattern was noted in all 48 cases but was predominant in 73% (35/48) of the cases. Immature metaplastic pattern was present in 71% (34/48) and was predominant in 27% (13/48). These features were not observed in negative control smears. 85% of cases (41/48) were interpreted as negative for epithelial cell abnormality. Two cases with predominantly glandular pattern (6%, 2/35) were interpreted as atypical glandular cells. Five cases with predominantly immature metaplastic pattern (38%, 5/13) showed checkerboard arrangement or rows of single cells with slightly larger atypical nuclei leading to interpretation as "atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion." The metaplastic cells with normoblast-like karyorrhectic apoptotic debris confined to the nuclear area were scattered among these cells in microglandular hyperplasia with metaplastic pattern.

Immunostaining of cytology smears: a comparative study to identify the most suitable method of smear preparation and fixation with reference to commonly used immunomarkers.

As an extension of our previous study (Shidham et al., Acta Cytol 2000;44:1015-1022), we evaluated the interference by methods of cytology smear preparation on the immunoreactivity of cytokeratin-7, cytokeratin-20, estrogen receptor, progesterone receptor, chromogranin, synaptophysin, and vimentin. Scrape cytology smears of 34 fresh specimens submitted for intraoperative consultation were studied. They were processed by three different methods--A: wet-fixed in 95% ethanol; B: air-dried saline rehydrated smears fixed in alcoholic formalin; and C: air-dried saline rehydrated smears fixed in 95% ethanol with 5% acetic acid. The intensity scores of immunostaining were estimated semiquantitatively and compared with corresponding formalin-fixed paraffin-embedded tissue sections (FPTS). Except vimentin, all immunomarkers showed higher intensity scores with method A or B than with method C. Vimentin showed the best results with method A. Our results indicate that the immunoreactivity pattern with each immunomarker is affected by the method of cytology smear processing. Most importantly, method C, which is the desired choice for cytomorphological staining, was not suitable for immunostaining.

FNAB cytology of chordoma masquerading as adenocarcinoma: case report.

We report a lesion of the mobile spine in a 77-yr-old white male who presented with lower back pain, radiating bilaterally to the legs, with numbness on walking and standing. Magnetic resonance imaging showed a large mass within L3-L4 vertebral bodies; however, chordoma was not suspected or suggested. Fine-needle aspiration biopsy (FNAB) of the mass revealed mostly blood with isolated flat clusters of polygonal rounded epithelial-like cells in a myxoid background. Immunohistochemistry could not be performed on the FNAB specimen due to inadequate material for cell-block. A limited immunocytochemistry panel was performed on one cytology smear. The tumor cells were immunoreactive for cytokeratin. During primary and expert evaluation, these features were interpreted as metastatic adenocarcinoma. Prostate and thyroid were suggested as possible primary sites. An extensive clinical and radiological search did not reveal a primary lesion. Four years later, the patient underwent surgical decompression and stabilization of his lumbar spine to avoid a catastrophic collapse of spine with neurological deficit. Histomorphological features and immunohistochemical studies at this time confirmed the lesion as chordoma. This case highlights the significance of considering chordoma in the differential diagnosis of FNAB cytology of spinal column lesions suggestive of adenocarcinoma, especially when the clusters of low-grade epithelioid cells with vacuolated cytoplasm in a myxoid background do not show epithelial structures such as papillae, glands, or acini.

Intrathoracic rosai-dorfman disease: hemorrhage with routine diagnostic procedure.

We present a case of a 33-year-old female with a slow growing, right peribronchial vascular mass and associated symptoms of progressive cough, dyspnea on exertion, and hemoptysis. On routine diagnostic flexible bronchoscopy with needle biopsy, the lesion hemorrhaged extensively requiring emergent thoracotomy, right lower and middle bilobectomy. The histopathology of the specimen was consistent with the rare and unusually located entity Rosai-Dorfman disease.

Enalapril mitigates focal alveolar lesions, a histological marker of late pulmonary injury by radiation to the lung.

The goal of our study was to identify a histological marker for testing countermeasures for mitigation of late radiation injury to the lung. Pulmonary fibrosis is currently the best described "late effect" in survivors of acute radiation pneumonitis. However, robust fibrosis does not develop in some rodent strains for years after a single dose of radiation to the whole thorax. We observed radiation-associated focal alveolar lesions that were rich in giant cells and macrophages containing cholesterol clefts in the lungs of irradiated WAG/RijCmcr rats. These lesions were first observed after pneumonitis, around 21 weeks after receiving a radiation dose of 13 Gy to the thorax but not until 71 weeks in unirradiated rats. The number of cholesterol clefts increased with time after irradiation through 64 weeks of observation, and at 30 weeks after 13 Gy, cholesterol clefts were associated with several indices of deterioration in lung function. The number of cholesterol clefts in irradiated lung sections were reduced by the angiotensin converting enzyme (ACE) inhibitor enalapril (25-42 mg/m²/day) from 18.7 ± 4.2/lung section to 6.8 ± 2.4 (P = 0.029), 5.2 ± 1.9 (P = 0.0051) and 6.7 ± 1.9 (P = 0.029) when the drug was started at 1 week, 5 or 15 weeks after irradiation, respectively, and continued. Similar lesions have been previously observed in the lungs of one strain of irradiated mice and in patients following radiotherapy. We propose that alveolar lesions with cholesterol clefts may be used as a histological marker of the severity of radiation lung injury and to study its mitigation in WAG/RijCmcr rats.

Fulminant multisystem non-langerhans cell histiocytic proliferation with hemophagocytosis: a variant form of Erdheim-Chester disease.

Hemophagocytosis (HP), a feature seen in malignant histiocytosis and infection- and lymphoma-associated disorders, has not been previously emphasized in Erdheim-Chester disease (ECD). Generally, ECD is recognized as a rare, systemic, non-Langerhans cell histiocytosis with a variable clinical course. Herein, we describe a unique case of multisystem non-Langerhans cell histiocytic proliferation with a fulminant clinical course (death occurred within 3 months of presentation) that showed prominent HP and extensive involvement of multiple organs, including the lungs, resulting in respiratory failure. Hemophagocytosis led to severe anemia that required transfusion and thrombocytopenia. Antemortem lung and bone marrow biopsy specimens revealed involvement by a histiocytic infiltrate with features highly suggestive of ECD and HP. Furthermore, the autopsy documented the presence of HP and the histiocytic infiltrate in multiple other organs. This case is best categorized as a variant form of ECD. Recognizing this variant has the following important implications: (1) HP may be a marker for fulminant clinical course in ECD, (2) the presence of HP does not exclude a diagnosis of ECD, and (3) ECD should be considered in the differential diagnosis of HP.

Distribution of chronic prostatitis in radical prostatectomy specimens with up-regulation of bcl-2 in areas of inflammation.

PURPOSE: We examined the anatomical relationship of chronic prostatitis with prostate cancer and benign prostatic hyperplasia (BPH) based on the hypothesis that there may be an association of prostatitis with these other entities that may involve up-regulation of bcl-2. MATERIALS AND METHODS: We examined 40 whole mount radical prostatectomy specimens for the presence and distribution of chronic inflammatory infiltrate. Immunostaining for bcl-2 was done in 10 cases. RESULTS: Chronic prostatitis was identified in all 40 cases with peripheral zone inflammation in 95% and transition zone inflammation in 87.5%. In all cases of transition zone inflammation the infiltrate was noted within and/or around BPH. Inflammatory infiltrate was microscopically associated with prostate cancer in 23 of the 40 cases (57.5%). In these 23 cases, there was no association of inflammation with Gleason score, preoperative prostate specific antigen, positive margins, or seminal vesicle invasion. Patients with BPH unassociated with prostatitis had significantly smaller prostate weight (median 32 gm.) and were younger (mean age 54.4 years) than those with BPH associated with prostatitis (median weight 40 gm. and mean age 61.4 years, p <0.05). Bcl-2 staining was intensified in benign glands within areas of prostatitis in all 10 cases examined. CONCLUSIONS: Chronic prostatitis is a common finding in radical prostatectomy specimens. Inflammation was associated with BPH and cancer but had a greater tendency to be associated with BPH. Bcl-2 was prominently expressed in areas of prostatitis. Our findings indirectly support a potential role for prostatitis in the pathogenesis of BPH.