Squamous Cell Metaplasia Research Articles

β-catenin mediates glandular formation and dysregulation of β-catenin induces hyperplasia formation in the murine uterus

Endometrioid adenocarcinoma is the most frequent form of endometrial cancer, usually developing in pre- and peri-menopausal women. beta-catenin abnormalities are common in endometrioid type endometrial carcinomas with squamous differentiation. To investigate the role of beta-catenin (Ctnnb1) in uterine development and tumorigenesis, mice were generated which expressed a dominant stabilized beta-catenin or had beta-catenin conditionally ablated in the uterus by crossing the PR(Cre) mouse with the Ctnnb1(f(ex3)/+) mouse or Ctnnb1(f/f) mouse, respectively. Both of the beta-catenin mutant mice have fertility defects and the ability of the uterus to undergo a hormonally induced decidual reaction was lost. Expression of the dominant stabilized beta-catenin, PR(cre/+)Ctnnb1(f(ex3)/+), resulted in endometrial glandular hyperplasia, whereas ablation of beta-catenin, PR(cre/+)Ctnnb1(f/f), induced squamous cell metaplasia in the murine uterus. Therefore, we have demonstrated that correct regulation of beta-catenin is important for uterine function as well as in the regulation of endometrial epithelial differentiation.

Rectal Squamous Cell Metaplasia in Crohnʼs Disease

Purpose: Case: 66 year old white male with history of long standing Crohn's disease presented for a surveillance colonoscopy. He was diagnosed in 1977 presenting with colo-vesicular fistula requiring a sigmoid resection. He subsequently developed peri-anal disease including fistulas and abscesses. Over the past several years the patient's disease was quiescent while receiving maintenance dosing of 6 mercaptopurine. He reported one to two formed, non-bloody bowel movements per day. His prior colonoscopy one year earlier revealed no evidence of active colitis and biopsies including the rectum did not show evidence of any dysplasia. A complete colonoscopy was performed which was normal with the exception of a uniform circumferential white-grayish discoloration extending 6 cm beyond the anal verge (Fig. 1). This finding simulated the appearance seen in Barrett's esophagus. Random biopsies were obtained every 10 cm from the colon using cold biopsy forceps. Other than the area in the rectum, the pathology revealed mild colonic inflammation. The proximal rectum revealed normal colonic mucosa, while pathology from the distal rectum revealed squamoglandular mucosa with focal acute cryptitis, without evidence of dysplasia or malignancy (Fig. 2). Discussion: The patient's findings reveals a rare case of squamous cell metaplasia in the rectum in a patient with long standing Crohn's disease. Review of literature revealed one such case in patient's with Crohn's disease, and two cases in patients with ulcerative colitis. The squamous cell metaplasia is likely due to chronic inflammation. This entity carries an increased risk for malignant transformation, however, due to the paucity of cases the magnitude of this risk is uncertain.Figure 2Figure 1Methods: N/A Results: N/A Conclusion: N/A

Functional study of nasal mucosa in endoscopic sinus surgery and its correlation to electron microscopy of cilia

The effect of functional endoscopic sinus surgery (FESS) was evaluated in 20 patients with chronic sinusitis. The physiological function of sinus mucosa and its mucociliary transport mechanism was assessed pre and post operatively in patients undergoing FESS by performing Saccharin clearance test. The effect of functional sinus surgery on nasal mucosa was evaluated using scanning electron microscopy and study of the ultrastructure of cilia in pre and post operative patients and correlation with histopathological examination. The mucociliary transport mechanism of the sinus mucosa improved 6 weeks following surgery. Histopathologically there was evidence of improvement in the ciliary population and decrease in inflammation, ulceration, fibrosis, vascular congestion, edema, squamous cell metaplasia, basement membrane thickening and polyp formation in comparison to the diseased mucosa sampled preoperatively. Scanning electron microscopic examination revealed considerable increase in the ciliary area as well as the orientation of cilia. Subjective improvement 6 weeks following surgery was confirmed by decrease in saccharin test time. This study revealed that FESS is an effective surgical procedure in chronic sinusitis and improves the overall function of the sinuses.

Cell Proliferation and DNA Content in Rat Urothelial Lesions after Repeat Intravesical Instillations of Mitomycin C and Bacillus Calmette-Guérin

Aim: To study cell proliferation and DNA content in urothelial lesions identified after repeated intravesical instillations of mitomycin C (MMC) and bacillus Calmette-Guérin (BCG) in normal rat urothelium. Material and Methods: A total of 45 rats were divided into nine equal groups: those intravesically instilled with MMC; those receiving BCG intravesically, and a control group intravesically instilled with a physiological solution of sodium chloride (SF). Animals were killed 1, 4 or 8 weeks after the last intravesical instillation. An immunohistochemical streptavidin-biotin-peroxidase technique was performed to investigate Ki-67 expression and the DNA ploidy status was measured using static cytometry. Results: In urothelium exposed to MMC lesions such as simple hyperplasia, dysplasia, carcinoma in situ(CIS), and squamous cell metaplasia were identified. The proliferation index presented values of 11.73, 22.43 and 31.46% in hyperplasias, dysplasias, and CIS, respectively (p < 0.05). The frequency of abnormal DNA content amongst those animals exhibiting simple hyperplasias 25% were aneuploid, in the dysplasia 85.2% were aneuploid (p = 0.041). CIS were all multiploid, and squamous cell metaplasias were all diploid. Animals treated with BCG and SF presented no urothelial lesions and a diploid DNA content. Conclusions: The aneuploid and multiploid DNA content and proliferation index observed in urothelial lesions identified after repeated intravesical instillations of MMC reflect a high degree of genomic instability in such lesions which in itself may lead to rapid regeneration of new phenotypes.

Giant urothelial carcinoma of unknown origin invading the sigmoid mesocolon – a case report

Summary Background Transitional cell carcinoma, also called urothelial carcinoma, is the most common malignancy of the urinary bladder. Additionally, it can develop in the lining of the renal pelvis, ureter, prostate and urethra. Exceptionally, cancer can arise from the urachus. Also primary transitional cell carcinoma of the endometrium or ovary is a rare entity. Aim The aim of this article was to present a case of giant urothelial carcinoma of unknown origin invading the sigmoid mesocolon. Case Report We report a rare case of urothelial carcinoma invading the sigmoid mesocolon in a 60-year-old female admitted to our department. The patient presented with a 25-cm intra-abdominal mass and 6-cm ulcerated lesion at the top of the umbilicus. Laparotomy was performed which demonstrated a huge polycystic and solid tumour of the sigmoid mesentery infiltrating the sigmoid colon and appendix. Appendectomy and resection of the tumour with an infi ltrated sigmoid loop were performed. A right ovarian cyst – not contiguous to the aforementioned tumour – was found at the time of the operation and excised. We also removed the 6-cm skin lesion in the umbilical area. Histopathological examination revealed urothelial carcinoma with squamous cell metaplasia of the sigmoid mesocolon with bowel and umbilical invasion. Concurrent desmoid cyst (mature teratoma) of the right ovary was found. Conclusions In conclusion, this patient with a sigmoid mesocolon invasion from urothelial carcinoma of unknown origin posed a diagnostic dilemma.

The different structures containing tight junction proteins in epidermal and other stratified epithelial cells, including squamous cell metaplasia

In stratified squamous epithelia constituent proteins of tight junctions (TJs) are not restricted to the zonula occludens-related structures of the uppermost living cell layer such as the stratum granulosum of the epidermis but TJ membrane proteins such as occludin and certain members of the claudin family as well as TJ plaque proteins, notably cingulin and protein ZO-1, have also been identified by immunofluorescence and immunoelectron microscopy in more basal layers where they form special cell–cell-connecting structures such as the “lamellated” and the “sandwich” junctions. In the present study, we describe another TJ protein-containing structure, the very small puncta occludentia (“stud junctions”), as the smallest identifiable TJ-like unit that occurs in most, perhaps all strata. We have also determined the specific distributions of TJ proteins in the cell layers of squamous cell metaplasias of the human bronchial tract. Moreover, we show that the occludin-related tetraspanin protein tricellulin- α connects and seals the membranes of adjacent “three corner” cell structures of the uppermost layer in keratinocytes growing in culture. We hypothesize the possible occurrence of tricellulin- β in more basal cell layers of keratinocyte cultures and the general occurrence of different tricellulin splice forms in stratified epithelia in situ, and discuss the possible functions of TJ proteins in stratified epithelia and tumors derived therefrom.

A Case of Sialolithiasis of the Buccal Gland with Chronic Sialadenitis in Japan

We describe herein the case of an 80-year-old man who suffered sialolithiasis and chronic sialadenitis of the minor salivary gland. Sialolithiasis occurs as a result of the presence of sialoliths in salivary ducts or parenchyma of salivary glands, but is rare in the minor salivary glands. The clinical and pathological findings of our case are also examined with reference to sialolithiasis in minor salivary glands described in the literature. Epithelial metaplasia, lobular inflammation and parenchymal atrophy were common findings. Follow-up examination was good. There was no recurrence of the buccal swelling. The pathological findings indicated that chronic inflammation and squamous cell metaplasia could be related to the etiological factors of this lesion or due to aging. The present case is the first instance of sialolithiasis of the buccal gland to be reported in Japan.

上顎洞粘膜病変におけるｃｙｃｌｏｏｘｙｇｅｎａｓｅ‐２発現の検討

Cyclooxygenases (COXs) are rate-limiting enzymes that initiate the conversion of arachidonic acid to prostanoids. COXs are classified into two isoforms: COX-1 and COX-2. COX-2 is an inducible isoform upregulated by proinflammatory cytokines. Recently, prominent COX-2 expression has been reported in several human cancers, including carcinoma of the colon, breast, lung, head and neck, and gallbladder. Overexpression of COX-2, which is involved in cell proliferation via prostaglandin E2 (PGE2) synthesis, may play a role in tumor progression. In this study, we immunohistochemically characterized COX-2 expression in various diseases of the maxillary sinus, including 5 cases of postoperative maxillary cyst, 5 of maxillary sinusitis, 5 of inverted papilloma, and 5 of maxillary sinus carcinoma. In addition, secretory phospholipase A2-V, CD3, CD20, and CD68 expression in these lesions was also examined to clarify the relation to COX-2 upregulation. COX-2 was not expressed in the ciliated columnar epithelium in sinusitis, but was expressed in squamous cell metaplasia in maxillary cyst and inverted papilloma. In carcinoma of the maxillary sinus, COX-2 was overexpressed in numerous cancer cells. The proportions of CD3 and CD68 positive cells in carcinoma were clearly lower than those in sinusitis. These results indicated that COX-2 expression correlates with squamous cell metaplasia and epithelial cell proliferation. The end product of the arachidonic acid cascade, PGE2, may be involved in downregulation of CD3 and CD68 and the proliferation of maxillary sinus carcinoma. Further studies of COX-2 inhibitors as potential antitumor agents in maxillary sinus carcinoma are warranted.

Expression of vascular cell adhesion molecule-1 (CD 106) in normal and neoplastic human esophageal squamous epithelium

Vascular cell adhesion molecule-1 (VCAM-1), a key receptor for the leukocyte-associated integrin (VLA4), is a crucial mediator of leukocyte adhesion and has co-stimulatory functions in inflammation at various organ sites. Specifically, VCAM-1/VLA4 interactions have been shown to play important roles in the setting of cutaneous immune responses, such as psoriatic lesions in humans and acute Graft-versus-Host-Disease in mice. VCAM-1 is generally expressed on activated endothelial cells in inflamed tissues, mediating endothelium-leukocyte interactions, leading to leukocyte diapedesis to the site of inflammation. We report novel and unexpected membrane expression of VCAM-1 in the basal squamous epithelial strata of the normal human esophagus and distinct patterns of epithelial expression in esophageal pathology. To further delineate the differential expression patterns of VCAM-1 in the esophageal epithelium, we examined specimens from squamous cell carcinoma (SCC), adenocarcinoma, and Barrett's columnar cell metaplasia. VCAM-1 was strongly expressed in squamous cell carcinoma, but not adenocarcinoma nor columnar epithelia in Barrett's esophagus. VCAM-1 expression was focally accentuated at sites characteristic of microscopic tumor invasion in SCC, pointing to a potential role of VCAM-1 in the development of metastasis. In addition, in vitro immunofluorescence studies using OE21 cells, an esophageal squamous epithelial cell line, displayed distinct VCAM-1 immunoreactivity confined to mitotic and dividing cells. Cell cycle arrest caused a significant decrease in VCAM-1 immunoreactivity in OE21 cells. These data suggest a previously unappreciated role for VCAM-1 in esophageal squamous epithelial homeostasis and pathology.

Massive squamous metaplasia of the thyroid gland – Report of three cases

Three cases of massive squamous cell metaplasia in Hashimoto's thyroiditis are reported. The patients were two men and one woman aged 24, 52, and 55 years, respectively. In all three patients, the glandular parenchyma was replaced by hypocellular fibrous tissue with scattered chronic inflammatory infiltrate. Follicular cells were almost absent; the majority of residual epithelial cells formed squamous nests that were partly solid and partly cystic. There were three types of epithelial cells – squamous, basaloid, and follicular, with oncocytic differentiation. The squamous and basaloid cells showed strong positivity high molecular weight (HMW) cytokeratin, moderate to strong expression of galectin-3 (2/3), and nuclear expression of p63 protein (2/3). The staining pattern of p63 was identical to that of HMW, with predominant positivity at the periphery of cell nests. In one case, weak but unequivocal positivity of thyroid transcription factor-1 also was present. We believe that metaplasia was caused by Hashimoto's thyroiditis. The cases presented here are extremely rare, and only two convincing similar cases have been reported in the English literature so far. They may represent a diagnostic pitfall and should not be misdiagnosed as a malignancy, in particular as squamous cell or mucoepidermoid carcinoma.

Transdifferentiation of Ciliated Cells during Repair of the Respiratory Epithelium

Since the lung is repeatedly subjected to injury by pathogens and toxicants, maintenance of pulmonary homeostasis requires rapid repair of its epithelial surfaces. Ciliated bronchiolar epithelial cells, previously considered as terminally differentiated, underwent squamous cell metaplasia within hours after bronchiolar injury with naphthalene. Expression of transcription factors active in morphogenesis and differentiation of the embryonic lung, including beta-catenin, Foxa2, Foxj1, and Sox family members (Sox17 and Sox2), was dynamically regulated during repair and redifferentiation of the bronchiolar epithelium after naphthalene injury. Squamous cells derived from ciliated cells spread beneath injured Clara cells within 6-12 h after injury, maintaining the integrity of the epithelium. Dynamic changes in cell shape and gene expression, indicating cell plasticity, accompanied the transition from squamous to cuboidal to columnar cell types as differentiation-specific cell markers typical of the mature airway were restored. Similar dynamic changes in the expression of these transcription factors occurred in ciliated and Clara cells during regeneration of the lung after unilateral pneumonectomy. Taken together, these findings demonstrate that ciliated epithelial cells spread and transdifferentiate into distinct epithelial cell types to repair the airway epithelium.

Histologic findings after gastrocystoplasty in rabbits

Purpose The aim of this study was to investigate the long-term histologic changes after bladder augmentation with gastric segment in an animal subject. Materials and Methods Gastrocystoplasty was performed in 13 young, 3-month-old male rabbits. Open biopsies were taken from the native bladder and the gastric segment preoperatively and at 3, 6, and 12 months postoperatively. Sections were examined with H&E and periodic acid–Schiff (PAS) staining. Indirect immune peroxidase method was additionally applied to detect the carcinoembrionic antigen, the proliferative activity, and the gene for the tumor protein p53 in the epithelium. Results On the native bladder, at the 3-month follow-up, polyps, mucosal edema, submucosal fibrosis, and squamous cell metaplasia were detected, which did not change during the follow-up. On the gastric segment, at the 3-month follow-up, parietal cell hyperplasia and inflammatory mucosal overgrowth were detected; at the 6-month follow-up, inflammation or atrophy of the gastric mucosa and colonic-type metaplasia was found. These alterations remained unchanged during later course of follow-up. Neither dysplasia nor malignancy was observed during the 12-month follow-up. Conclusions The present study supports the clinical observations of low cancer risk after gastrocystoplasty and may indicate different effect of gastric secretion on uroepithelium and that of urine on gastric mucosa.

Use of mometasone furoate aqueous nasal spray in the treatment of rhinitis medicamentosa: An experimental study

We aimed to investigate, histopathologic changes in the nasal mucosa of guinea pig's after prolonged administration of oxymetazoline and the development of rhinitis medicamentosa, and the efficacy of mometasone furoate aqueous nasal spray and saline in reversing the ultrastructural changes attributable to rhinitis medicamentosa. In the study, 24 male guinea pigs (500 to 600 gr) were used. Oxymetazolin (0.05%) was sprayed into the nasal cavities of the guinea pigs 3 times daily for 8 weeks. At the end of this period, 6 guinea pigs were killed and examined to make sure that the animals had developed rhinitis medicamentosa. The remaining guinea pigs were randomly divided into 3 groups. In the first group, one spray-puff of 0.05% mometasone furoate aqueous nasal spray (50 microg) was applied twice daily for 14 days. In the second group, saline solution (0.9% NaCl) was applied twice daily for 14 days. No treatment was performed in the third group. At the end of the treatment period, nasal mucosal changes were evaluated by light microscopy and electron microscopy. After oxymetazolin application for 8 weeks, the main histologic changes were edema, congestion, proliferation of subepithelial glands, and squamous cell metaplasia. After topical mometasone furoate aqueous spray application for 2 weeks, the edema fluid was found to diminish markedly. In the saline and no treatment groups, edema and congestion continued. In these groups of guinea pigs, fibrosis has been seen in the nasal mucosa. We found that mometasone furoate nasal spray was effective against experimentally induced rhinitis medicamentosa in guinea pigs. Mometasone furoate nasal spray may have value in the treatment of patients with rhinitis medicamentosa.

Atypical Glandular Cells in Cervical Smear During Pregnancy and Postpartum Period

The 2001 Bethesda System defines atypical glandular cells (AGC) as glandular cell abnormalities that are distinct from adenocarcinoma or adenocarcinoma in situ.1 Before 2001, a spectrum of glandular cell abnormalities in cervical smears was grouped under atypical glandular cells of undetermined significance (AGUS) and defined as glandular cells exhibiting changes beyond reactive or reparative changes, but lacking unequivocal features of invasive adenocarcinoma.2 The incidence and clinical significance of AGUS have been extensively reported, 3–6 however, studies reporting AGUS smears in pregnancy and postpartum period are very limited. Chhieng and colleagues7 have reported the largest number of AGUS smears in pregnancy and postpartum period (n=35). Among the 13,361 smears performed during the 3-year study period, this group reported a 0.26% incidence rate with a mean patient age of 29. Of the 35 patients with AGUS smears, 8 patients were lost to follow up, 17 were referred for colposcopy and biopsy, and 10 had repeated smears. For those who underwent colposcopy and biopsy, five patients had histologically proven cervical intraepithelial lesions. The others had benign pathologies including squamous cell metaplasia, endocervical or endometrial polyps, Arias-Stella reactions and microglandular hyperplasia. Two of the 10 patients had persistent abnormalities on repeated smears but their outcomes were not reported. The authors reported the incidence of significant pathology in this study as 29%. However, the incidence rate of significant pathology was calculated on the basis of the 17 cases referred for colposcopy and biopsy only, and did not include the patients being followed with repeated smears which would reduce the rate of significant pathology to less than 20%. Two other studies have been reported on pregnancy related AGUS, although these involved smaller numbers of patients. Michael and colleagues8 reported 26 cases of AGUS during pregnancy or postpartum period, most of which were followed with repeated cervical smears after 3 to 6 months. Biopsies were performed in the postpartum period only if atypia persisted on repeat smears. Eight patients had colposcopy directed biopsies and only 2 patients were diagnosed with squamous cell intraepithelial lesions. Kim and colleagues9 reported a large study of 326 patients: 21 were diagnosed with AGUS during pregnancy or within 8 weeks postpartum. Only one of the 21 patients had significant pathology showing carcinoma in situ, though the method of follow-up was not specified. From the studies described above, the incidence of significant pathology following an abnormal glandular cytology on cervical smear during pregnancy or postpartum period was not as high as has been demonstrated in the non-pregnant population (31% to 48%).4,10,11 The observed lower incidence could be explained by 1) over-diagnosis of AGUS during pregnancy and postpartum period, and 2) younger age in patients having pregnancy-related AGUS smears. A number of reports have emphasized pregnancy-related cellular changes and their diagnostic pitfalls.13–17 Decidual cells, trophoblasts, and Arias-Stella reactions frequently cause confusion in the interpretation of cervical smears of pregnant patients. Distinguishing between Arias-Stella cells and cells of glandular abnormalities can be difficult because the morphologic characterization of the former is poor.17 It is therefore essential for the pathologists evaluating the smear to know the pregnancy status of the patient. Misdiagnosis could be minimized by the awareness of the physiological changes associated with pregnancy. The mean age of patients having AGUS during pregnancy or postpartum period was only available in one of the papers discussed above. The mean age of these patients was much lower (mean age=27) than in non-pregnant populations (ages 44 to 50),6,9,10,12 and could partially explain the lower incidence of significant pathology in pregnancy-related AGUS as the risk of malignancy is lower in younger women. From the very limited evidence currently available, no clear guidelines for the management of atypical glandular cells detected in cervical smears during pregnancy or postpartum period can be developed. Sub-classification of atypical glandular cells into favor neoplasia or not otherwise specified as required in the 2001 Bethesda System would help the colposcopists in making clinical diagnoses.1 Communication between pathologists and colposcopists is fundamental. Colposcopy during pregnancy is a safe procedure and colposcopy directed biopsy, in experienced hands, helps exclude significant cervical pathologies for selected cases. If malignancy is not evident from initial colposcopic evaluation, follow-up colposcopic and cytologic surveillance are acceptable methods for management during pregnancy. However, endocervical sampling is not advisable during pregnancy. Cone biopsy during pregnancy increases the risk of pre-term, pre-labor rupture of membranes and should only be performed if malignancy is highly suspicious.18 After 8 weeks postpartum, invasive investigation can safely be performed and patients should be managed according to the 2001 Bethesda consensus guidelines.1

Squamous cell metaplasia of the nasopharyngeal epithelium and its association with adult-onset otitis media with effusion

ConclusionThe common association between adult-onset otitis media with effusion (AO-OME) and squamous cell metaplasia (SCM) of the epithelium of Rosenmüller's fossa, which is near the Eustachian tube orifice, implies the predictive role of metaplasia, which probably compromises the drainage function of the middle ear.ObjectiveTo determine the effects of nasopharyngeal epithelial changes (SCM) on AO-OME. AO-OME is a multifactorial and insidious disease that may necessitate detailed investigation, i.e. biopsy of the nasopharynx, because of possible underlying nasopharyngeal malignancy.Material and methodsFifty-two patients with AO-OME (study group) and 29 with a unilateral neck mass in the posterior triangle without AO-OME (control group) were enrolled. Nasopharyngeal biopsies taken from all subjects were evaluated with regard to surface epithelial changes of the nasopharynx.ResultsNasopharyngeal biopsies revealed SCM in 34/52 patients (65%) in the study group and 9/29 (31%) in the control group (p<0.05). During the follow-up period, recurrence of effusion occurred in 56% of the group with SCM and 22% of the group without it.

Effects of Topical Antiglaucoma Medications on the Ocular Surface

The side effects of topical antiglaucoma medications and their preservatives range from ocular discomfort to sight-threatening alterations of the ocular surface. Conjunctival hyperemia, decreased tear production and function, and superficial punctate keratitis are among the most common signs seen on routine clinical examination. Squamous cell metaplasia and changes in cell morphology have been demonstrated by impression cytology studies and evaluation of biopsy specimens, and inflammatory effects are documented by the presence of inflammatory markers. The adverse effects of topical antiglaucoma eyedrops interfere with the treatment of glaucoma on two levels: first, the discomfort produced by the eye drops discourages patient compliance; and, second, long-term treatment with eyedrops is associated with a higher failure of filtration surgery. The detailed mechanism of inflammatory response and/or direct toxicity of eye drops has yet to be determined, but it may vary with the different classes of eye drops, different preservatives, and durations of treatments. Upcoming multicenter trials for new antiglaucoma eye drops should specifically evaluate ocular surface effects.

Autologous Rectal Mucosal Grafts on the Conjunctiva of Healthy Rabbits

We evaluated the feasibility and viability of 10×5 mm autologous rectal mucosal grafts on the superior bulbar conjuctival surface of 25 albino rabbits. After enucleation, histopathological studies revealed a mean goblet cell count of 190 cells per ×400 field and squamous cell metaplasia did not exceed 20%. Rectal mucosa transplantation into the conjuctiva of healthy rabbit’s eyes is possible.

Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma: A Clinicopathologic and Immunophenotypic Analysis of 22 Cases

The diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is an uncommon tumor making up about 2% of all papillary thyroid carcinomas. Previous studies have not comprehensively evaluated these tumors in a large series of patients. Twenty-two cases of DSV-PTC diagnosed between 1970 and 2000 were identified in the files of the AFIP. Histologic and immunohistochemical features were evaluated and patient follow-up was obtained. The tumors affected 14 females and 8 males, aged 6 to 49 yr (mean, 18 yr), with males presenting at a mean older age than females (24 vs 14 yr). Symptoms included an enlarging mass in the thyroid, present for a mean of 9.5 mo. While a dominant tumor was identified in a single lobe, bilateral disease was common (n = 16). The dominant mass ranged in size from 1.7 to 5.8 cm in diameter (mean, 3.8 cm). Histologically, all cases demonstrated a papillary carcinoma (conventional, solid, or follicular pattern) diffusely involving the gland. Extrathyroidal extension, lymphocytic thyroiditis, squamous metaplasia, increased fibrosis/sclerosis, and psammoma bodies were present to a variable degree. Both the papillary carcinoma and squamous metaplasia cells were strongly immunoreactive with CK19, thyroglobulin, and TTF-1. An increased number of S-100 protein immunoreactive dendritic cells were recognized. p53 was increased (>15%) in the tumor cells in 12 patients, while Ki-67 was increased in the tumor cells in two patients. Perithyroidal and cervical lymph node metastasis occurred in 18 (82%) patients. All metastases demonstrated histologic features similar to the primary. Complete resection (thyroidectomy in 18 patients) with lymph node dissection, yielded a 95% 5-yr survival without evidence of disease. One patient died of disease after a malignant transformation of the squamous metaplasia into squamous cell carcinoma. The recognition of DSV-PTC can be made with the following features: classic to solid foci of PTC, lymphocytic thyroiditis, squamous metaplasia, increased fibrosis, and innumerable psammoma bodies. DSV-PTC is more biologically aggressive than conventional PTC, but the patients' survival is not significantly different. This diagnosis should lead the clinician to aggressively manage these patients (thyroidectomy and lymph node dissection) in an effort to achieve an excellent long-term clinical outcome.

Human neutrophil defensins and secretory leukocyte proteinase inhibitor in squamous metaplastic epithelium of bronchial airways.

The aim of this study was to analyze a possible contribution of human neutrophil defensins and secretory leukocyte proteinase inhibitor (SLPI) to the induction of airway epithelial changes such as squamous cell metaplasia. The presence of these molecules and the number of proliferating (Ki-67-positive) epithelial cells was analyzed by immunohistochemistry in bronchial epithelium from subjects with (n = 15) or without (n = 14) chronic obstructive pulmonary disease (COPD). Our data demonstrate higher numbers of defensin-positive (p = 0.0001), elastase-positive (p = 0.0001) and Ki-67-positive (p = 0.0001) cells in areas with squamous cell metaplasia as compared to areas with intact or damaged epithelium, while the reverse was observed for SLPI expression (p = 0.002). No differences were observed between subjects with or without COPD, nor between current smokers and those that had stopped smoking. These data are in line with a role of defensins in the hyperproliferative phenotype of squamous metaplastic lesions in the airways. This role does not seem to be restricted to patients with COPD.

CFR-1 receptor as target for tumor-specific apoptosis induced by the natural human monoclonal antibody PAM-1

The human monoclonal antibody PAM-1 was isolated from a patient with stomach cancer. The germ-line coded IgM antibody identifies a recently described 130 kDa variant of CFR-1 (cysteine-rich fibroblast growth factor receptor 1). This CFR-1/PAM-1 receptor is post-transcriptionally modified and over-expressed on human epithelial tumors and carcinoma pre-cancer lesions such as H. pylori induced gastritis, intestinal metaplasia and dysplasia of the stomach, ulcerative colitis-related dysplasia and adenomas of the colon, Barrett metaplasia and dysplasia of the esophagus, squamous cell metaplasia and dysplasia of the lung and cervical intraepithelial neoplasia. Furthermore, the expression of CFR-1/PAM-1 correlates with the proliferation rate and increases with the grade of malignancy. This study demonstrates that the human monoclonal antibody PAM-1 inhibits cell growth and induces apoptosis, in vitro and in vivo. Both, the unique tumor-specific expression of the CFR-1/PAM-1 receptor and the growth inhibitory effect of the PAM-1 antibody makes this combination a good diagnostic and therapeutic tool for all kinds of epithelial cancers and precursor lesions.