Toward personalized medicine of lung cancer: response to nontargeted therapy in invasive pulmonary adenocarcinoma as a function of tumor cell differentiation.

We evaluated clinical parameters, histomorphology, and thyroid transcription factor 1 (TTF-1) immunoreactivity in 40 epidermal growth factor receptor (EGFR) mutation- and anaplastic lymphoma kinase (ALK) rearrangement-negative invasive pulmonary adenocarcinomas. Tumors were histomorphologically quantitated by a pulmonary pathologist and TTF-1 immunohistochemistry applied. EGFR mutation and ALK rearrangement status was determined with polymerase chain reaction/DNA sequencing and fluorescence in situ hybridization, respectively. Treatment response was related to type of treatment (P < .005) and clinical stage (P = .001). EGFR mutation- and ALK rearrangement-negative pulmonary adenocarcinomas containing papillary/micropapillary histology showed greater morphologic heterogeneity (P < .001), greater TTF-1 immunoreactivity (P = .004), and were more common in treatment responders (P < .05). These findings support that patients with pulmonary adenocarcinomas that are subject to nontargeted therapies may respond to treatment as a function of tumor cell differentiation with TTF-1 as a potential biomarker of this response.

Primary malignant fibrous histiocytoma (myxofibrosarcoma/pleomorphic sarcoma not otherwise specified) of the breast: clinicopathologic study of 19 cases.

We present 19 cases of primary breast malignant fibrous histiocytoma (MFH) or myxofibrosarcoma/pleomorphic sarcoma not otherwise specified, the largest series to date, and compare our results with those in the literature to better define MFH in this anatomical location. Twenty-seven cases (MFH, myxofibrosarcoma, or pleomorphic sarcoma not otherwise specified) were reviewed using World Health Organization and French Federation of Cancer Centers criteria. Inclusion required location within breast parenchyma without extensive chest wall involvement. Morphological features were recorded, and immunohistochemistry was applied. Clinical data were extracted from patients' medical records. Clinically, there was 1 male patient. Of 15 patients with follow-up, 5 (33% overall) died of disease within an average of 7 months after diagnosis. Distant metastases and older patient age were associated with poor survival. Storiform-pleomorphic subtype was most common (10/19) with myxofibrosarcoma (6/19) and giant cell subtype (1/19) also observed. Unique lymphocyte-rich (1/19) and pleomorphic hyalinizing angiectatic tumor-like (1/19) morphologies are presented. Immunohistochemistry demonstrated expression of CD68 (71%), focal smooth muscle actin (36%), with rare focal estrogen and progesterone receptor immunoreactivity. All cases were negative for CD34, S-100 protein, desmin 33, and keratins, including CK7, CK20, CK5/6, and CK18. Malignant fibrous histiocytoma occurs as a primary lesion in breast parenchyma. Attention to morphological detail and immunohistochemistry avoids misdiagnosis. Entrapped breast ductal epithelium should not be misinterpreted as the epithelial component of a biphasic tumor. A florid lymphoid response should not be confused with metaplastic carcinoma. Pleomorphic hyalinizing angiectatic tumor-like features may be observed in MFH. Our study confirms the presence of MFH in breast and presents unique morphological observations of primary breast MFH.

Granulomatous reaction to pneumocystis jirovecii: clinicopathologic review of 20 cases.

To better characterize the clinical and pathologic features of granulomatous reaction to Pneumocystis jirovecii, we reviewed 20 cases of this uncommon response. Patients included 15 males and 5 females (mean age 52 y). The most common symptom was dyspnea (5 of 14). Primary medical diagnoses included human immunodeficiency virus/acquired immunodeficiency syndrome (7 of 20), hematopoietic (6 of 20), and solid malignancies (4 of 20). Radiology findings included nodular (8 of 16) and diffuse (5 of 16) infiltrates and solitary nodules (3 of 16). Diagnostic procedures with the highest yield were open lung biopsy (13 of 20) and autopsy (5 of 20); false-negative results were most common on bronchial washings/brushings, bronchoalveolar lavage, fine needle aspiration, and transbronchial biopsy. Follow-up showed resolution of disease (6 of 13), death from disease (6 of 13), and death from unknown cause (1 of 13). Histologically, clusters of Gomori methenamine silver-positive (20 of 20) Pneumocystis organisms were identified in all cases. Organisms were identified within well (16 of 20) and poorly (4 of 20) formed necrotizing (16 of 20) and non-necrotizing (4 of 20) granulomas ranging in size from 0.1 to 2.5 cm (mean 0.5 cm); granulomas were multiple (18 of 20) or single (2 of 20). Giant cells (11 of 20), a fibrous rim (8 of 20), and eosinophils (6 of 20) were seen. Foamy eosinophilic exudates were present centrally within some granulomas (5 of 20). Cystic spaces (1 of 20) and calcification (1 of 20) were rare. Only one case demonstrated classic intra-alveolar foamy exudates containing Pneumocystis. Granulomatous P. jirovecii pneumonia occurs most commonly in males with human immunodeficiency virus/acquired immunodeficiency syndrome, hematopoietic, and solid malignancies. The diagnosis may be overlooked as conventional radiologic and pathologic features are absent. When suspected, open lung biopsy is most likely to yield diagnostic material. Attention to organism morphology avoids misdiagnosis as Histoplasma.

Del(5q) is associated with clinical and histological parameters in small cell neuroendocrine lung carcinoma.

To elucidate the relationship between del(5q) and the clinical and histological features of small cell neuroendocrine lung carcinoma, 33 tissue samples from patients with this tumor were evaluated. By using fluorescence in situ hybridization, del(5q) was identified in almost 50% of cases (15/33, 45%). Clinically, patients with tumors showing del(5q) were older (mean age = 71 years) with a correspondingly greater pack-year smoking history (mean = 61) than patients with tumors (mean age = 59 years, mean pack-years = 44) without del(5q). Histologically, tumors with del(5q) had a greater frequency of spindle cell morphology (11/14 [79%] vs 6/16 [38%], P < .025) than those without del(5q). This is the first study to find an association between del(5q) and tumor histology in small cell neuroendocrine lung carcinoma.

Primary pulmonary and mediastinal synovial sarcoma: a clinicopathologic study of 60 cases and comparison with five prior series.

Primary pulmonary and mediastinal synovial sarcoma is rare and poses a diagnostic challenge particularly when unusual histological features are present. We present 60 cases of primary pulmonary and mediastinal synovial sarcoma (29 male and 27 female subjects; mean age, 42 years) and compare our results with five prior series to better define unusual histological features. Clinically, patients with mediastinal synovial sarcoma were younger with a male gender bias. Radiologically, tumors were well delineated with distinctive magnetic resonance imaging features and little vascular enhancement. In all, 21/46 patients died of disease within 5 years. Histologically, all tumors had dense cellularity, interlacing fascicles, hyalinized stroma, and mast cell influx. Hemangiopericytoma-like vasculature (48/60), focal myxoid change (30/60), and entrapped pneumocytes (23/60) were seen. Calcification was not prevalent (10/60). Unusual histological features included Verocay body-like formations (7/60), vague rosettes (6/60), well-formed papillary structures (3/60), adenomatoid change (3/60), and rhabdoid morphology (2/60). Immunohistochemistry demonstrated expression of pancytokeratin (39/58), epithelial membrane antigen (29/53), cytokeratin 7 (26/40), cytokeratin 5/6 (5/7), calretinin (15/23), CD99 (19/23), bcl-2 (24/24), CD56 (11/11), S-100 (9/51), and smooth muscle actin (8/32). In total, 92% (36/39) of primary pulmonary and mediastinal synovial sarcomas studied were positive for t(x;18). In conclusion, our study confirms the clinical, histological, immunohistochemical, and molecular data from previous large series of primary pulmonary and mediastinal synovial sarcoma. Compared with soft tissue synovial sarcoma, primary pulmonary and mediastinal synovial sarcoma has less calcification, less obvious mast cell influx, and less radiologic vascularity, but similar magnetic resonance imaging features, percentage of poorly differentiated tumors, and number of t(x;18)-positive tumors. Awareness of focal unusual histology can prevent misdiagnosis particularly in t(x;18)-negative tumors.

Malignant optic nerve glioma (glioblastoma multiforme): A case report and literature review.

Primary gliomas of the optic nerve are very rare. We report a case of a 59-year-old male with sudden vision loss diagnosed with malignant optic nerve glioblastoma multiforme. Magnetic resonance imaging revealed thickening of optic tracts, chiasm, and hypothalamus. Histologically, the tumor was composed of glial cells with pleomorphic nuclei and areas of vascular proliferation and necrosis. The patient died eight weeks after initial presentation. In addition to our case, 30 previously reported cases of malignant optic nerve glioma are reviewed.

CD99 immunoreactivity in atypical fibroxanthoma and pleomorphic malignant fibrous histiocytoma: a useful diagnostic marker.

Atypical fibroxanthoma (AFX), a benign lesion, and pleomorphic malignant fibrous histiocytoma (MFH) are thought to represent points along the same neoplastic spectrum but with different prognoses and treatments. Diagnosis based on histology and clinical parameters alone is sometimes difficult, and a reliable cost-effective immunohistochemical marker to help distinguish these lesions would be beneficial. The diagnosis of AFX or MFH was based upon published clinical and microscopic criteria. Formalin-fixed, paraffin-embedded tissues of 17 cases of AFX and 26 cases of MFH were immunostained with monoclonal antibody to CD99. For all cases, CD99 expression was scored on a four-tiered scale: negative, weak (1+), moderate (2+), or strong (3+). Two pathologists blinded to tumor diagnoses and type of immunostain evaluated each case independently. The interobserver correlation coefficient was calculated. Seventeen patients with AFX (16 males and one female; mean age = 79) and 26 patients with MFH (16 males and 10 females; mean age = 60) were included. AFX lesions were from the head and the face, mean size = 1.5 cm, and MFH lesions were from the head, the neck, the trunk, and the upper/lower extremities, mean size = 5.2 cm. The 17 cases of AFX demonstrated moderate or strong (2 to 3+) immunoreactivity with CD99, compared to nine of 26 (35%) MFH cases (chi-square = 18.38; p < 0.001; interobserver correlation coefficient = 0.83). Of these, 16 of 17 (94%) AFX cases stained diffusely with CD99, while only four of 26 (15%) MFH cases stained diffusely. Control slides were adequate. Our study demonstrated that CD99 can help distinguish AFX from MFH, in addition to other immunohistochemistry as well as clinical and histologic criteria.

Primary cutaneous follicle center lymphoma of the arm with a novel chromosomal translocation t(12;21)(q13;q22): a case report.

We report a reciprocal translocation between the long arms of chromosomes 12 and 21, t(12;21)(q13;q22), in a patient with primary cutaneous follicle center lymphoma. Follicle center lymphoma of the skin and follicle center cell lymphoma of the lymph node are morphologically and immunophenotypically very similar. However, the clinical behavior and prognosis of these tumors are different due to the molecular basis of these malignancies. Follicle center cell lymphoma of the lymph node is determined by the presence of a unique translocation between chromosomes 14 and 18, t(14;18)(q32;q21), BCL-2-JH gene rearrangement, that is not present in primary cutaneous follicle center lymphomas. Chromosomal translocations in the primary skin lymphomas have not been previously reported. We hope that our discovery of a new translocation t(12:21)(q13q22) will encourage further investigation into the molecular basis of this translocation and other cytogenetic abnormalities in primary cutaneous B-cell lymphomas.