Abraxane, an albumin-bound paclitaxel nanoparticle formulation, is superior to conventional paclitaxel preparations because it has better efficacy against unresectable pancreatic cancer. Previous reports suggest that this better efficacy of Abraxane than conventional paclitaxel preparation is probably due to its transport through Gp60, an albumin receptor on the surface of vascular endothelial cells. The increased tumor accumulation of Abraxane is also caused by the secreted protein acid and rich in cysteine in the tumor stroma. However, the uptake mechanism of Abraxane remains poorly understood. In this study, we demonstrated that the delivery of Abraxane occurred via different receptor pathways from that of endogenous albumin. Our results showed that the uptake of endogenous albumin was inhibited by a Gp60 pathway inhibitor in the process of endocytosis through endothelial cells or tumor cells. In contrast, the uptake of Abraxane-derived HSA was less affected by the Gp60 pathway inhibitor but significantly reduced by denatured albumin receptor inhibitors. In conclusion, these data indicate that Abraxane-derived HSA was taken up into endothelial cells or tumor cells by a mechanism different from normal endogenous albumin. These new data on distinct cellular transport pathways of denatured albumin via gp family proteins different from those of innate albumin shed light on the mechanisms of tumor delivery and antitumor activity of Abraxane and provide new scientific rationale for the development of a novel albumin drug delivery strategy via a denatured albumin receptor.
Isosulfan blue is not available for clinical use in Malaysia. This study describes the use of methylene blue as an alternative to isosulfan blue in colorectal sentinel node mapping.
Breast ductal carcinoma in-situ (DCIS) is increasingly being diagnosed as a result of screening mammography and better pathological recognition. With this and the rising breast cancer incidence in Singapore, DCIS is poised to become a bigger part of surgical practice. Principles of screening, diagnosis and management of DCIS have also been rapidly evolving. Against this background, a clinicopathological audit of recent cases of DCIS in our centre was performed.
Molecular alterations in KRAS, BRAF, PIK3CA, and PTEN have been implicated in designing targeted therapy for colorectal cancer (CRC). The present study aimed to determine the status of these molecular alterations in Malaysian CRCs as such data are not available in the literature. We investigated the mutations of KRAS, BRAF, and PTEN, the gene amplification of PIK3CA, and the protein expression of PTEN and phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110α) by direct DNA sequencing, quantitative real-time PCR, and immunohistochemistry, respectively, in 49 CRC samples. The frequency of KRAS (codons 12, 13, and 61), BRAF (V600E), and PTEN mutations, and PIK3CA amplification was 25.0% (11/44), 2.3% (1/43), 0.0% (0/43), and 76.7% (33/43), respectively. Immunohistochemical staining demonstrated loss of PTEN protein in 54.5% (24/44) of CRCs and no significant difference in PI3K p110α expression between CRCs and the adjacent normal colonic mucosa (p = 0.380). PIK3CA amplification was not associated with PI3K p110α expression level, but associated with male cases (100% of male cases vs 56% of female cases harbored amplified PIK3CA, p = 0.002). PI3K p110α expression was significantly higher (p = 0.041) in poorly/moderately differentiated carcinoma compared with well-differentiated carcinoma. KRAS mutation, PIK3CA amplification, PTEN loss, and PI3K p110α expression did not correlate with Akt phosphorylation or Ki-67 expression. KRAS mutation, PIK3CA amplification, and PTEN loss were not mutually exclusive. This is the first report on CRC in Malaysia showing comparable frequency of KRAS mutation and PTEN loss, lower BRAF mutation rate, higher PIK3CA amplification frequency, and rare PTEN mutation, as compared with published reports.
In the present study, we evaluated the association between the TP53BP1 Glu353Asp and T-885G polymorphisms and breast cancer risk as well as with the clinicopathological characteristics of the patients. Genotyping of these polymorphisms was performed on 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy using PCR-RFLP method in a hospital-based Malaysian population. Breast cancer risk was not observed among women who were heterozygous (OR(adj) = 0.887; 95% CI, 0.632-1.245) or homozygous (OR(adj) = 1.083; 95% CI, 0.595-1.969) for Asp allele, and those carriers of Asp allele (OR(adj) = 0.979; 95% CI, 0.771-1.243). Similarly, women who were TG heterozygotes (OR(adj) = 1.181; 95% CI, 0.842-1.658) or GG homozygotes (OR(adj) = 1.362; 95% CI, 0.746-2.486) and carriers of G allele (OR(adj) = 1.147; 95% CI, 0.903-1.458) were not associated with increased risk of breast cancer. Asp allele genotype was significantly associated with ER negativity (p = 0.0015) and poorly differentiated tumours (p = 0.008), but G allele genotype was not associated with the clinicopathological characteristics. In conclusion, Glu353Asp and T-885G polymorphic variants might not have an influence on breast cancer risk, thus might not be potential candidates for cancer susceptibility. Glu353Asp variant might be associated with tumour aggressiveness as defined by its association with ER negativity and poorly differentiated tumours.
Poly(amidoamine) dendrimers (PAMAM) are well-defined, highly branched, nanoscale macromolecules with numerous active amine groups on the surface. PAMAM dendrimer can enhance the solubility of hydrophobic drugs, and with numerous reactive groups on the surface PAMAM dendrimer can be engineered with various functional groups for specific targeting ability. However, in physiological conditions, these amine groups are toxic to cells and limit the application of PAMAM. In the recent years, polyethylene glycol (PEG) conjugation has been the most widely used approach to reduce the toxicity of the active group on dendrimer surface. PEG molecules are known to be inert, non-immunogenic, and non-antigenic with a significant water solubility. PEGylated PAMAM-mediated delivery could not only overcome the limitations of dendrimer such as drug leakage, immunogenicity, hemolytic toxicity, systemic cytotoxicity but they also have the ability to enhance the solubilization of hydrophobic drugs and facilitates the potential for DNA transfection, siRNA delivery and tumor targeting. This review focuses on the recent developments on the application and influence of PEGylation on various biopharmaceutical properties of PAMAM dendrimers.
STATEMENT OF SIGNIFICANCE: It is well established that dendrimers have demonstrated promising potentials for drug delivery. However, the inherent toxicity poses challenges for its clinical translation. In this regard, PEGylation has helped mitigate some of the toxicity concerns of dendrimers and have paved the way forward for testing its translational potentials. The review is a collection of articles demonstrating the utility of PEGylation of the most studied PAMAM dendrimers. To our knowledge, this is a first such attempt to draw reader's attention, specifically, towards PEGylated PAMAM dendrimers.
Primary malignant melanoma arising in the oesophagus is a rare condition with a dismal prognosis. The diagnosis is often made following surgical resection even though the endoscopic features may be pathognomonic. The classical treatment is oesophagectomy even though the advanced disease stage at the time of presentation and aggressive biological behaviour of the tumour usually results in a fatal outcome. We report the case of a male patient initially diagnosed with squamous oesophageal carcinoma and treated with conventional neo-adjuvant chemo-radiotherapy. Poor clinical and radiological response resulted in a review of the original histology confirming a diagnosis of primary malignant melanoma of the oesophagus. The subsequent alteration in management conferred the patient an improved quality of life. A short review of the literature on primary malignant melanoma of the oesophagus supplements this case report.
BACKGROUND: Extraskeletal (soft tissue) chondromas are rare neoplasms. They are seen most frequently in the soft tissues of hands and feet. A chondroma occurring in the breast is exceedingly uncommon. We present a case of pure chondroma of the breast in a young woman in whom fine needle aspiration (FNA) cytologic features suggested a cartilaginous neoplasm.
CASE: A 28-year-old woman presented with a mobile lump in the left breast. Mammography showed a high-density nodule without microcalcifications. A clinical diagnosis of fibroadenoma was made. A differential diagnosis was obtained on FNA. Excisional biopsy of the lump showed the histopathologic features of chondroma. There was no recurrence or appearance of new lesion during 13 months of follow-up.
CONCLUSION: Chondroma of the breast shows FNA cytologic features of cartilaginous tumor, but specific tumor typing may not be possible. This case highlights the difficulties that may arise in FNA diagnosis of cartilaginous tumor especially when it occurs at an unusual site. Awareness of the cytologic features combined with clinical and radiologic findings should guide the cytopathologist to make correct diagnosis of this neoplasm.
Matched MeSH terms: Breast Neoplasms/pathology*; Soft Tissue Neoplasms/pathology*
BACKGROUND: Pilomatrixoma (pilomatrixoma, calcifying epithelioma of Malherbe) is a relatively uncommon, benign neoplasm arising from the skin adnexa. The tumor can cause diagnostic difficulty not only for the clinician but also for the cytologist.
CASE: A 62-year-old woman presented with a right submandibular swelling of 4 months' duration. The clinical findings were highly suspicious for malignancy. A fine needle aspiration biopsy was performed. Three preliminary differential diagnoses were offered: mucoepidermoid carcinoma of the submandibular salivary gland, squamous cell carcinomatous deposit in a submandibular lymph node and calcifying odontogenic tumor. Computed tomography demonstrated no bony lesion. No primary site of squamous cell carcinoma could be identified. An excisional biopsy of the swelling was performed, and the histologic diagnosis of pilomatrixoma was made.
CONCLUSION: The cytologic presentation of pilomatrixoma of the right submandibular region can masquerade as that of a malignant tumor, in this case mucoepidermoid carcinoma, squamous cell carcinoma or odontogenic tumor. This case delineates the cytomorphologic features of pilomatrixoma that may mimic carcinoma.
OBJECTIVE: To analyze the cytologic features of nipple discharge and fine needle aspiration (FNA) cytologic smears from breast lesions reported as showing papillary features and to correlate them with histopathologic features.
STUDY DESIGN: The study group consisted of FNA smears and/or nipple discharge smears from 65 breast lesions diagnosed on cytology as duct papilloma, papillary lesion, fibrocystic condition, fibroadenoma, papillary neoplasm or papillary carcinoma. Cytomorphologic features assessed included cellularity, cell pattern (clusters, papillary, 3-dimensionality, etc.) and cell characteristics (monomorphism, pleomorphism, apocrine change, plasmacytoid features). Histological material was available for review and cytohistologic correlation in all cases.
RESULTS: Forty-six specimens were FNA smears, and 16 were nipple discharge smears; in 3 cases FNA and nipple discharge cytologic smears were available for review. Cytologic study could predict the presence of a papillary pattern in all neoplasms with pure or focal papillary differentiation. There was an overlap in cytomorphologic features between papillary and nonpapillary benign lesions as well as between benign and malignant papillary neoplasms. Frank blood in the aspirate, cell dissociation and atypia, however, were more frequent in the last.
CONCLUSION: Overlap of cytologic features in nonneoplastic and neoplastic benign papillary lesions and between benign and malignant papillary neoplasms necessitates histologic evaluation in all cases diagnosed as papillary on cytology. Since 49.2% of lesions showing papillary features on cytology prove to be malignant, all cases reported as papillary on cytology should be excised urgently for histologic assessment.
BACKGROUND: Carcinosarcoma (sarcomatoid carcinoma) is a rare tumor with a high predilection for the aerodigestive tract. Cytologic diagnosis of metastatic carcinosarcoma has been reported in very few cases.
CASE: An 84-year-old woman presented with a 2-cm-diameter, right cervical lymph node that was referred for fine needle aspiration cytology (FNAC). She had received radiotherapy for a palatal squamous cell carcinoma 2 years earlier. The FNAC smears had a sarcomatoid appearance. Repeat fine needle aspiration was performed, with cytologic and immunocytochemical staining. Careful consideration of the cytologic and immunophenotypic features led to an impression of carcinosarcoma. Histologic sections of the palatal biopsy that had been previously diagnosed as squamous cell carcinoma were reviewed, and a final diagnosis of carcinosarcoma was established.
CONCLUSION: Metastasis of rare lesions, such as carcinosarcoma may be confusing and difficult to diagnose on FNAC, especially when the cytologic sample shows a predominantly sarcomatoid component. The difficulty is compounded when the sarcomatoid component happens to have been overlooked on the initial histologic assessment. With representative cytologic sampling, immunocytochemical staining and review of the histologic material, the correct diagnosis was achieved in this case.
To type breast carcinomaon on fine needle aspiration cytology (FNAC) material and correlate the results with histologic typing, to grade breast carcinoma on FNAC material and correlate the findings with Bloom-Richardson histologic grading, and to determine the estrogen receptor (ER) status in cases of breast carcinoma by immunocytochemical (ICC) staining of FNA cytologic material and correlate the findings with ER status, as determined by immunohistochemical (IHC) staining of tissue sections.
STUDY DESIGN: Seventy-seven cases of breast carcinoma diagnosed on FNAC formed the basis of this study. Typing was done in all cases on the basis of cytologic features and grading in 62. (Fifteen cases were special types of breast carcinoma). In all cases, ER status was determined by immunostaining of cytologic smears. Results of tumor typing, grading and ER status on cytologic material were compared with the results of histologic typing, grading and immunostaining of histologic material obtained from mastectomy or wide excision specimens.
RESULTS: Tumor typing was accurate in 73 of 77 cases (94.8%). Fifteen of 18 cases that were cytologically grade 3 were confirmed on histology, while 3 proved to be grade 2. Of 40 cytologic grade 2 cases, 26 were confirmed on histology, while 14 cases were grade 3. Three of 4 cytologically grade 1 cases were confirmed on histology while 1 was grade 2. The overall accuracy for cytologic grading was 71% (44 of 62 cases). Thirty-seven of 40 ER-positive cases (92.5%) were labeled ER positive on ICC. One case was ER negative on cytology, while in 2 cases the cellularity of the cytologic smear was insufficient to assess ER expression. Thirty-seven cases were negativefor ER on IHC. Nine of these showed ER positivity on ICC, 26 were negative, and 2 had cellularity that was inadequate for assessment of ER. Sensitivity and specificity rates for ER detection on ICC were 97.4% and 74.3%, respectively.
CONCLUSION: Tumor typing, grading and evaluation of ER status on FNA C material in breast carcinomas are simple, quick and moderately reliable techniques that compare and correlate favorably with histologic typing, grading and ER status on IHC.
BACKGROUND: Leiomyosarcoma of the breast is a rare neoplasm. We present a case of primary leiomyosarcoma of the breast in a middle-aged female in whom fine needle aspiration cytologic features suggested sarcoma.
CASE: A 55-year-old female presented with a rapidly growing breast lump of 1 month's duration. On examination, an ulcerating, 12 x 10 cm tumor was seen involving the lower medial and lateral quadrants of the right breast. Fine needle aspiration cytology showed variably sized, dissociated and loosely clustered polygonal, plump and spindle cells with pale blue cytoplasm and vesicular nuclei that were round, oval or irregular. Occasional giant forms and nucleolated and mitotic cells were present. A single cluster of benign ductal cells was seen. The tumor cells did not express immunocytologic reactivity to estrogen receptor protein. A cytologic diagnosis of sarcoma was given with differential diagnoses of metaplastic carcinoma and malignant phyllodes tumor. Histologic study established the diagnosis of leiomyosarcoma. Leiomyosarcoma of the breast shows fine needle aspiration cytologic features of sarcoma, but specific tumor typing may not be possible, especially when the cytologic material is inadequate for ancillary staining required to distinguish leiomyosarcoma from metaplastic carcinoma and malignant phyllodes tumor.
BACKGROUND: Squamous papillary craniopharyngioma is a distinct entity, and its cytologic features may be misleading. Because of the rarity of this tumor, this case is being reported with a note on the cytologic features.
CASE: A 56-year-old Malay man who had 1-month history of generalized lethargy was admitted for altered sensorium. On examination, he was found to have neck stiffness, bilateral papilledema and generalized atrophy of muscles, with reduced power in all limbs. Magnetic resonance imaging of the brain showed a solid mass in the third ventricle causing obstructive hydrocephalus. Intraoperative cytology of the mass diagnosed intraventricular meningioma. However, the final histopathologic examination revealed squamous papillary craniopharyngioma.
CONCLUSION: Craniopharyngioma, squamous papillary type, is a rare entity and usually occurs in adults as an intraventricular solid tumor. Awareness of this entity will aid in arriving at the correct cytologic diagnosis.
BACKGROUND: Teratoma of the thyroid in adults is extremely rare, and most are malignant. Only nine cases have been adequately documented in the English-language literature, and there are no reports detailing the fine needle aspiration (FNA) cytologic characteristics.
CASE: A 32-year-old female presented with a left-sided nodular thyroid mass with left cervical lymphadenopathy. FNA cytology of the thyroid and lymph nodes was done. The cytologic and immunocytochemical features were that of a small round cell tumor with neuroepithelial (NE) differentiation, metastasizing to the cervical nodes. Microscopic study of the thyroidectomy specimen showed a tumor showing an NE pattern with occasional islands of squamous and cuboidal epithelium, leading to a diagnosis of malignant teratoma.
CONCLUSION: Knowledge of FNA cytologic features of rare but highly malignant lesions like thyroid teratomas allow early recognition so that suitable and possibly aggressive treatment protocols can be adopted in the hope of prolonging survival.
OBJECTIVE: To examine the fine needle aspiration cytologic features of invasive lobular carcinoma of breast and to discuss problems that may occur in cytodiagnosis.
STUDY DESIGN: Fine needle aspiration cytologic smears from 21 cases of invasive lobular carcinoma (ILC) of breast were subjected to detailed cytomorphologic analysis. Features studied included pattern of cells, size of cells, nuclear placement, pleomorphism, presence of intracytoplasmic lumina (ICL) and signet ring cells.
RESULTS: Cellularity was generally moderate or high, and the pattern was predominantly or partly dissociated in 86% of cases. Rosettelike pattern was discerned in alveolar-type ILC. Cell size was usually small or intermediate, with nuclei placed eccentrically in most cases. ICLs with or without signet ring cells were present in 12 cases (57%).
CONCLUSION: A cytologic picture consisting of predominantly dissociated small or intermediate-sized tumor cells with eccentric nuclei, with some of the cells showing ICLs, is highly suggestive of ILC. Indian file pattern, another characteristic feature of ILC, is, however, focal and inconsistent. Variant patterns of ILC may show other cytologic features, such as rosettelike pattern (alveolar variant of ILC) or large cell pattern (pleomorphic variant of ILC) and may consequently be difficult to categorize on cytologic smears.
BACKGROUND: The diverse range of diseases that affect the salivary glands may lead to problems and pitfalls in cyto-diagnosis. While false negative diagnosis of cystic salivary gland tumors is well known, false positive cytodiagnosis in nonneoplastic salivary cysts is less well documented.
CASE: An 85-year-old female presented with a painless left parotid gland swelling of three months' duration. Fine needle aspiration cytology yielded fluid, smears of which showed keratinizing squamous cells with nuclear atypia leading to a cytologic diagnosis of cystic squamous cell carcinoma. A total radical parotidectomy followed. Histopathologic study showed cystic dilatation of many of the salivary ducts, which were lined with metaplastic squamous epithelium that showed atypia. There was no evidence of squamous cell carcinoma.
CONCLUSION: Squamous metaplasia is known to occur in benign salivary gland lesions, such as pleomorphic adenoma and Warthin's tumors, as well as in salivary duct cysts and necrotizing sialometaplasia. However, atypical squamous metaplasia of salivary duct cysts mimicking squamous cell carcinoma on cytology is unusual.