Hashimoto's Thyroiditis

Background

Hashimoto's thyroiditis is the prototypical example of autoimmune thyroiditis. This latter term has been used to describe a class of diseases in the thyroid all sharing an autoimmune origin. These diseases include Hashimoto's thyroiditis, Grave's disease, and various chronic lymphocytic thyroditis with various hormonal presentations. It is hypothesized that there is a defect in the cellular immune system with disturbance of the suppressor T cells. A randomly mutated clone of the helper T cells then produces interferon-alpha inducing production of B cells which can produce autoantibodies. Interferon interacts with the thyroid follicular epithelial cells inducing HLA-DR expression. This action allows these epithelial cells to act as antigen-presenting cells, further stimulating the immune response. The autoantibodies produced by the B cell serve to further the damage on the thyroid gland. Like other autoimmune disorders, there is an increased risk of malignancy, with a B-cell malignant lymphoma, the most common to arise within the gland. A rare association is a sclerosing mucoepidermoid carcinoma which arises with fibrosing Hashimoto's disease.

The thyroid gland is usually enlarged in early or active disease. However, with time and progressive fibrosis, atrophy may supervene. A recent classification system has attempted to organize the spectrum of autoimmune thyroid disease.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

DISEASE ASSOCIATIONS CHARACTERIZATION

CELIAC DISEASE

Markers of potential coeliac disease in patients with Hashimoto's thyroiditis.

Valentino R, Savastano S, Maglio M, Paparo F, Ferrara F, Dorato M, Lombardi G, Troncone R.

CNR, Experimental Endocrinology and Oncology Center (CEOS), Department of Cellular and Molecular Biology and Pathology, University Federico II, Naples, Italy.
Eur J Endocrinol 2002 Apr;146(4):479-83 Abstract quote
OBJECTIVE: Coeliac disease (CD) is associated with autoimmune thyroid disease. Gluten sensitivity represents a spectrum, with at one end cases with severe gluten-dependent enteropathy, and at the other subjects with minor signs of deranged mucosal immune response. The aim of this paper was to look for signs of minor small bowel injury and immunohistochemical markers of gluten sensitivity in a group of patients with Hashimoto's disease.

SUBJECTS AND METHODS: Fourteen patients with Hashimoto's thyroiditis without serological evidence of CD underwent immunohistochemical analysis of jejunal biopsies.

RESULTS: In 6/14 cases (43%) an increased density of gammadelta T cell receptor bearing intra-epithelial lymphocytes was found. In 6/14 (43%) signs of mucosal T cell activation (presence of interleukin 2 (IL2) receptor (CD25) on lamina propria T cells and/or expression of human lymphocyte antigen (HLA)-DR molecules on crypt epithelial cells) were noted. In 4 out of 6 such cases, HLA haplotypes were described in association with CD.

CONCLUSION: A significant proportion of patients with Hashimoto's thyroiditis present signs of 'potential' CD and of activated mucosal T cell immunity. The gluten dependence of such findings remains to be ascertained.

GRANULOMA ANNULARE

Localized granuloma annulare and autoimmune thyroiditis in adult women: A case-control study.

Vazquez-Lopez F, Pereiro M Jr, Haces JA, Lopez MA, Sanchez TS, Coto TF, Oliva NP, Toribio J.

Departments of Dermatology, Central University Hospital, University of Oviedo, and Complejo Hospitalario Universitario, University of Santiago de Compostela.

J Am Acad Dermatol 2003 Apr;48(4):517-20 Abstract quote
BACKGROUND: The coexistence of granuloma annulare (GA) and autoimmune thyroiditis (AT) has been sporadically observed in female patients, but the significance of this rarely reported association remains uncertain.

OBJECTIVE: To investigate for the first time the frequency and type of thyroid disease in adult women with localized granuloma annulare (LGA) compared with a matched control group.

METHODS: Twenty-four adult women with histology-proven LGA and a control group of 100 age-matched female patients with other unrelated cutaneous diseases were screened for thyroid disease in a tertiary teaching hospital in northern Spain. Laboratory evaluation included routine hematologic and chemistry analysis, antinuclear antibody, rheumatoid factor, thyroid function test (sensitive thyroid-stimulating hormone [TSH]), thyroid autoantibody levels, and antibodies to thyroid peroxidase in all patients and controls. Thyroid hormones (free triiodothyroxine and free thyroxine) were measured when TSH value was abnormal. AT was defined as hypothyroidism (TSH value >5 mU/L) and in addition to elevated antithyroid antibodies or characteristic thyroid biopsy. The results were compared using Fisher's exact test.

RESULTS: Statistical evaluation of the findings obtained in this study showed mainly that the frequency of AT was increased significantly in the group of adult women with LGA (3/24, 12%) compared with the matched control group (1/100) (Fisher's exact test: P =.022).

CONCLUSION: Although little can be inferred from a single investigation, the results of this pilot study indicate an association between LGA and AT in adult female patients, supporting the theory that at least a subset of GA belongs to the spectrum of autoimmune diseases.

LYMPHOCYTIC COLITIS

Increased colonic intraepithelial lymphocytes in patients with Hashimoto's thyroiditis.

Cindoruk M, Tuncer C, Dursun A, Yetkin I, Karakan T, Cakir N, Soykan I.

Department of Gastroenterology, Gazi University Medical School, Ankara, Turkey.
J Clin Gastroenterol 2002 Mar;34(3):237-9 Abstract quote
BACKGROUND: Hashimoto's thyroiditis is an autoimmune thyroid disorder. Lymphocytic colitis and collagenous colitis are characterized by diarrhea with normal endoscopic findings. Autoimmune disorders are common in Hashimoto's thyroiditis and lymphocytic colitis. The aim of this study was to investigate the incidence of lymphocytic colitis in patients with Hashimoto's thyroiditis.

STUDY: Fifty patients with well-documented Hashimoto's thyroiditis were included. Twenty patients with nonulcer dyspepsia served as a control group. Five of 50 patients with Hashimoto's thyroiditis reported intermittent diarrhea, whereas no patients had diarrhea in the control group. All patients and the control group underwent total colonoscopy, and multiple colonoscopic biopsies were performed.

RESULTS: We found that 40% (20 of 50) of Patients with Hashimoto's thyroiditis had histologic findings consistent with lymphocytic colitis, and one patient in the control group had lymphocytic colitis (p < 0.01). The mean number of intraepithelial lymphocytes was 34.4/100 epithelial cells in these 20 patients, whereas the mean number of intraepithelial lymphocytes was 12.3/100 epithelial cells in the other 30 patients with Hashimoto's thyroiditis (p < 0.05).

CONCLUSIONS: There was a higher incidence of histologic findings of lymphocytic colitis in patients with Hashimoto's thyroiditis, although most of the patients were clinically asymptomatic. This finding suggests that lymphocytic colitis may have an asymptomatic clinical course and should encourage further clinical investigations to better anticipate the relationship between autoimmune disorders.

PATHOGENESIS CHARACTERIZATION

NITRIC OXIDE SYNTHASE

Up-regulation of cyclooxygenase-2 expression in lymphocytic thyroiditis and thyroid tumors: significant correlation with inducible nitric oxide synthase.

Nose F, Ichikawa T, Fujiwara M, Okayasu I.

Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Am J Clin Pathol 2002 Apr;117(4):546-51 Abstract quote
To cast light on relations of cyclooxygenase-2 (COX-2) expression to lymphocytic thyroiditis and thyroid tumorigenesis, protein levels were immunohistochemically assessed and compared with inducible nitric oxide synthase (iNOS) in a total of 181 cases: follicular adenoma, 23; well-differentiated papillary carcinoma, 85; poorly differentiated papillary carcinoma, 25; anaplastic carcinoma, 7; and follicular carcinoma, 41. In addition, 72 specimens of normal follicular epithelia and 36 of lymphocytic thyroiditis were used as control samples.

Immunohistochemical results were confirmed in 2 cases each of normal thyroid, lymphocytic thyroiditis, and well-differentiated and poorly differentiated papillary carcinoma, by Western blotting assay. Stepwise increments in overexpression of COX-2 and iNOS were revealed in epithelial cells of lymphocytic thyroiditis, follicular adenoma, and papillary carcinoma; normal thyroid epithelium showed little expression. A significant positive correlation between the 2 enzymes was found with all cases.

Enhanced expression of both COX-2 and iNOS suggests important roles in the inflammatory processes underlying lymphocytic thyroiditis and thyroid tumorigenesis.

RET/PTC

Prevalence of RET/PTC Rearrangements in Hashimoto's Thyroiditis and Papillary Thyroid Carcinomas.

Nikiforova MN, Caudill CM, Biddinger P, Nikiforov YE.

Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA.
Int J Surg Pathol 2002 Jan;10(1):15-22 Abstract quote
The relationship between Hashimoto's thyroiditis (HT) and follicular cell-derived thyroid cancer remains unclear. Recently, 2 studies reported a 95% prevalence of RET/PTC rearrangements in histologically benign tissue affected by HT, suggesting that multiple occult tumors exist in HT patients with high frequency.

We tested the prevalence of RET/PTC rearrangements in 26 HT, in 6 papillary carcinomas arising in the background of HT, and in 27 papillary carcinomas not associated with HT. We detected no RET/PTC rearrangements in HT or papillary carcinomas arising in the background of HT, in contrast to a 33% prevalence among papillary carcinomas not associated with HT. However, the expression of wild-type RET was found in more than half of papillary carcinomas.

These results suggest that, if the association between HT and thyroid cancer exists, its molecular basis is different from RET/PTC rearrangement.

CLINICAL VARIANTS CHARACTERIZATION

HASHIMOTO'S ENCEPHALOPATHY

Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment.

Kothbauer-Margreiter I, Sturzenegger M, Komor J, Baumgartner R, Hess CW.

Neurologische Klinik, Inselspital, Bern, Switzerland.
J Neurol 1996 Aug;243(8):585-93 Abstract quote
Six patients with Hashimoto thyroiditis (HT) and associated encephalopathy (HE) are described and compared with 14 well-documented cases retrieved from the literature. HE typically affects patients when they are euthyroid and, in an appropriate clinical situation, antithyroid autoantibodies are the main indicators of HE. Since clinical features of HE are unspecific, other aetiologies such as infectious, metabolic, toxic, vascular, neoplastic, and paraneoplastic causes have to be excluded.

Our own six cases and those from the literature show that two types of initial clinical presentation can be differentiated: a vasculitic type with stroke-like episodes and mild cognitive impairment in nine patients, and a diffuse progressive type with dementia, seizures, psychotic episodes or altered consciousness in 11 patients. These types may overlap, particularly in the long-term course without treatment. Response to steroids was usually excellent with complete remission in 80%. Eighteen of the 20 patients were women. Characteristic, though unspecific, findings were abnormal EEG (90%) and CSF (80%).

Together with quantitative neuropsychological testing, these proved sensitive for monitoring the efficacy of therapy. Conversely, antithyroid autoantibody titres did not correlate with the severity or type of clinical presentation. The link between HE and HT is not clear. A pathogenetic role for antithyroid autoantibodies in the central nervous system seems unlikely.

Encephalopathy as the presenting symptom of Hashimoto's thyroiditis.

Watemberg N, Willis D, Pellock JM.

Child Neurology Division, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.

J Child Neurol 2000 Jan;15(1):66-9 Abstract quote
In recent years, encephalopathy has increasingly been recognized as a complication of Hashimoto's thyroiditis.

It can begin abruptly as a stroke-like event, acute seizures, or confusion, or as an insidious decline in cognitive function. Most reported cases have been on adult patients, although this encephalopathy does affect children as well.

This form of encephalopathy should be considered in the differential diagnosis of children and adults with unexplained neurologic deterioration. We describe the case of a child in whom acute encephalopathy was the presenting symptom of Hashimoto's thyroiditis.

Hashimoto's encephalopathy.

Chen HC, Marsharani U.

Division of Endocrinology, University of California at San Francisco, USA.
South Med J 2000 May;93(5):504-6 Abstract quote
Hashimoto's encephalopathy is a subacute condition associated with autoimmune thyroiditis.

Its presentation varies from focal neurologic deficits to global confusion. Unlike encephalopathy associated with hypothyroidism, Hashimoto's encephalopathy responds to steroid therapy and not thyroxine replacement.

Encephalopathy associated to autoimmune thyroid disease: a more appropriate term for an underestimated condition?

Canton A, de Fabregas O, Tintore M, Mesa J, Codina A, Simo R.

Department of Endocrinology, Hospital Vall d'Hebron, Ps. Vall d'Hebron 119-129 8&z.ausco; Planta, 08035, Barcelona, Spain.
J Neurol Sci 2000 May 1;176(1):65-9 Abstract quote
Hashimoto's encephalopathy is a severe and rather infrequent clinical condition initially described in patients suffering from chronic lymphocytic thyroiditis. Its origin is still controversial but it can be agreed to have an autoimmune etiology. In fact, its most characteristic finding is the high titre of antithyroid antibodies, especially antimicrosomal.

We describe three cases of Hashimoto's encephalopathy and establish a relationship between the clinical status, the antithyroid antibody levels and its response to corticosteroid treatment. There was an excellent response to corticosteroid treatment in all three cases. Interestingly, one case was associated with Graves' disease.

Given this, and after the review of the literature, we believe that the term 'encephalopathy associated to autoimmune thyroid disease' could be more appropriate to define this entity.

Finally, we suggest that autoimmune thyroid encephalopathy must be suspected in the face of unaccounted acute or subacute encephalopathy with high levels of antithyroid antibodies.

HISTOPATHOLOGICAL VARIANTS CHARACTERIZATION

GENERAL
Hum Pathol 1982;22:980

Lymphoplasmacytic infiltrate with secondary germinal centers and variable fibrosis. Thyroid follicles are usually small and may be atrophic. Oncocytic, clear cell, and squamous metaplasia is common within the follicular cells.

Classification of Chronic Lymphocytic Thyroiditis Classic Hashimoto's thyroiditis

Mixed
Lesser inflammatory infiltrate with minimal fibrosis
May be eu-, hypo-, or hyper-thyroid

Hyperplastic
Glandular hyperplasia with small lymphocytic reaction
Usually hyperthyroid

Focal
Focal lymphocytic reaction
Usually normothyroid (euthyroid)

VARIANTS

FIBROSING
There is an interesting variant known as a fibrosing variant, occurring in 10% of cases.

It is more common in elderly individuals who have goiters and hypothyroidism

Dense keloid-like fibrosis with severe follicular atrophy, and squamous metaplasia of the follicular epithelium.

SPECIAL STAINS/
IMMUNO-HISTOCHEMISTRY CHARACTERIZATION

GENERAL

Characterization of the lymphoid infiltrate in Hashimoto thyroiditis by immunohistochemistry and polymerase chain reaction for immunoglobulin heavy chain gene rearrangement.

Hsi ED, Singleton TP, Svoboda SM, Schnitzer B, Ross CW.

Department of Pathology, University of Michigan Medical School, Ann Arbor, USA.
Am J Clin Pathol 1998 Sep;110(3):327-33 Abstract quote
A close relationship between Hashimoto thyroiditis (HT) and low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) has been shown.

We used immunohistochemistry to study paraffin sections from 40 unselected cases of HT and scored cases according to the lymphoid infiltrate and presence of lymphoepithelial lesions (LELs). Clonality was assessed by kappa/lambda immunohistochemistry and polymerase chain reaction for immunoglobulin heavy chain gene rearrangement (IgH PCR). Histologic findings were compared with 2 cases of primary thyroid MALT-type lymphoma. In HT, the lymphoid infiltrate consisted predominantly of T cells in all cases; B cells, associated with germinal centers, did not have the appearance of marginal zone cells.

All cases had identifiable T-cell LELs; immunohistochemistry confirmed inconspicuous, rare B-cell LELs in 13 of 40 cases. In all cases, plasma cells were polyclonal and IgH PCR showed a polyclonal pattern. Clinical follow-up was available for 34 patients. Lymphoma developed in none. In contrast, a B-cell predominant infiltrate of marginal zone cells was present in the MALT-type lymphomas that was not confined to germinal centers. Cytokeratin stains demonstrated severe loss of epithelial elements and destructive LELs. LELs are not, in isolation, a useful criterion for distinguishing low-grade MALT-type lymphoma of the thyroid from HT.

Features associated with low-grade MALT-type lymphoma include a predominance of B cells, marked loss of epithelial elements, and destructive LELs composed of marginal zone B cells. Unselected cases of HT do not contain monoclones detectable by IgH PCR.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA

Sclerosing mucoepidermoid thyroid carcinoma with eosinophilia. A distinctive low-grade malignancy arising from the metaplastic follicles of Hashimoto's thyroiditis.

Chan JK, Albores-Saavedra J, Battifora H, Carcangiu ML, Rosai J.

Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Am J Surg Pathol 1991 May;15(5):438-48 Abstract quote
Eight cases of a distinctive low-grade carcinoma of the thyroid gland occurring in a background of Hashimoto's thyroiditis are reported. The patients were women presenting with a painless thyroid mass. Grossly, the tumors were white, homogeneous, firm, and usually ill defined.

Histologically, strands and small nests of squamoid tumor cells exhibiting mild to moderate nuclear pleomorphism, distinct nucleoli, and pale cytoplasm infiltrated an abundant, dense fibrohyaline stroma. Foci of definite squamous differentiation and small pools of mucin were often found within the tumor nests. The neoplastic cells were immunoreactive for cytokeratin, but not for thyroglobulin or calcitonin. The stroma and many of the tumor islands were infiltrated by eosinophils in all cases. Extrathyroidal extension occurred in five cases and lymph node metastases in one.

This tumor seems to arise from the benign squamous nests sometimes associated with mucin deposition found in Hashimoto's thyroiditis and thought to be the result of metaplastic changes of the follicular epithelium. It shares several morphologic features with cases previously reported as mucoepidermoid carcinoma of the thyroid, but it differs from them in other respects. The differential diagnosis includes undifferentiated/squamous cell carcinoma, intrathyroidal thymic carcinoma, and direct extension or metastasis of carcinoma from other organs.

Sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid: report of two patients, one with distant metastasis, and review of the literature.

Sim SJ, Ro JY, Ordonez NG, Cleary KR, Ayala AG.

Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Hum Pathol 1997 Sep;28(9):1091-6 Abstract quote
Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a recently recognized malignant neoplasm of the thyroid gland. Two additional cases of this condition which occurred in a 70-year-old woman and a 69-year-old woman are presented.

The case of the 70-year-old woman (patient 1) is the first report of distant metastasis, besides lymph node metastasis, for this type of tumor. The patient initially presented with a thyroid mass, and the thyroid gland with surrounding cervical lymph nodes was removed. Because of focal keratin "pearl" formation, the tumor was misinterpreted as a metastatic squamous cell carcinoma to the thyroid. Approximately 4 years later, the patient developed a left supraclavicular mass and lung densities. A pathological fracture of the right humeral head followed, and the left supraclavicular mass recurred along with newly developed subcutaneous nodules on the chest wall and arm. Open lung and bone biopsies revealed metastatic SMECE, which was morphologically identical to that of the thyroid mass. The 69-year-old woman (patient 2) had, in 1983, undergone thyroidectomy with left radical neck dissection; this had been diagnosed as follicular carcinoma of the thyroid with lymph node involvement. After multiple isolated lymph nodes metastases, the patient developed locally extensive, recurrent tumor that showed microscopic features of SMECE. Review of the previous thyroid tumor and lymph nodes revealed the same type of histology.

To our knowledge, only a single report containing eight cases of this distinctive carcinoma of the thyroid has been published. Herein we describe characteristic morphological features of two additional cases of this rare malignancy, one with distant metastasis, and we review the related literature.

PROGNOSIS AND TREATMENT CHARACTERIZATION

TREATMENT

SURGERY

Surgical treatment of Hashimoto's thyroiditis. Personal experience.

Carli AF, Lottini M, Testa M, Neri A.
Minerva Chir 2002 Apr;57(2):117-22 Abstract quote
BACKGROUND: To report personal experience in the surgical treatment of Hashimoto's thyroiditis.

METHODS. Eight patients (7 females, 1 male, mean age 48 years old) referred to our Institu-tion with diagnosis of Hashimoto's thyroiditis have been studied. All patients were evaluated by determination of serum thyroid hormones and of anti-thyreoglobulin and anti-microsomal antibodies; ultrasound and scintigraphic scans of the gland were performed in all cases and a cytological examination of fine needle aspiration (FNAC) of the nodules was evaluated. Diagnosis of Hashimoto's thyroiditis was suspected on the basis of clinical and laboratory data and was confirmed by cytology and histology on surgical specimens. Preoperative FNAC showed a Hashimoto's thyroiditis with thyroid differentiated carcinoma in 3 cases (37.5%), Hashimoto's thyroiditis in 1 case and chronic thyroiditis in 4 cases (50%). Seven patients underwent surgery, while 1 patient received a medical treatment; we performed 6 total thyroidectomies and 1 hemithyroidectomy. Histology on surgical specimens confirmed the diagnosis of Hashimoto's thyroiditis in all cases; in 3 patients an associated papillary thyroid carcinoma was found.

RESULTS: Postoperative mortality was absent; no major postoperative complications (laryngeal nerve paralisis or permanent hypocalcemia) were recorded. Only 2 mild transient hypocalcemias have been observed.

CONCLUSIONS: Total thyroidectomy is the technique of choice in surgical treatment of Hashimoto's thyroiditis, a self-immune pathology which involves the whole gland and has a high correlation with differentiated thyroid carcinoma (37.5%). Total thyroidectomy warrants a radical and definitive control of the disease, without risk of relapse, with a low incidence of major complications, in experienced hands, and anyway lower than the morbility due to reinterventions.

Hum Pathol 1974;5:161-170.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Autoimmune disorders

Mucoepidermoid Carcinoma of the Thyroid Gland

Thyroid Gland

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DISEASE ASSOCIATIONS	CHARACTERIZATION
CELIAC DISEASE
Markers of potential coeliac disease in patients with Hashimoto's thyroiditis. Valentino R, Savastano S, Maglio M, Paparo F, Ferrara F, Dorato M, Lombardi G, Troncone R. CNR, Experimental Endocrinology and Oncology Center (CEOS), Department of Cellular and Molecular Biology and Pathology, University Federico II, Naples, Italy.	Eur J Endocrinol 2002 Apr;146(4):479-83 Abstract quote OBJECTIVE: Coeliac disease (CD) is associated with autoimmune thyroid disease. Gluten sensitivity represents a spectrum, with at one end cases with severe gluten-dependent enteropathy, and at the other subjects with minor signs of deranged mucosal immune response. The aim of this paper was to look for signs of minor small bowel injury and immunohistochemical markers of gluten sensitivity in a group of patients with Hashimoto's disease. SUBJECTS AND METHODS: Fourteen patients with Hashimoto's thyroiditis without serological evidence of CD underwent immunohistochemical analysis of jejunal biopsies. RESULTS: In 6/14 cases (43%) an increased density of gammadelta T cell receptor bearing intra-epithelial lymphocytes was found. In 6/14 (43%) signs of mucosal T cell activation (presence of interleukin 2 (IL2) receptor (CD25) on lamina propria T cells and/or expression of human lymphocyte antigen (HLA)-DR molecules on crypt epithelial cells) were noted. In 4 out of 6 such cases, HLA haplotypes were described in association with CD. CONCLUSION: A significant proportion of patients with Hashimoto's thyroiditis present signs of 'potential' CD and of activated mucosal T cell immunity. The gluten dependence of such findings remains to be ascertained.
GRANULOMA ANNULARE
Localized granuloma annulare and autoimmune thyroiditis in adult women: A case-control study. Vazquez-Lopez F, Pereiro M Jr, Haces JA, Lopez MA, Sanchez TS, Coto TF, Oliva NP, Toribio J. Departments of Dermatology, Central University Hospital, University of Oviedo, and Complejo Hospitalario Universitario, University of Santiago de Compostela.	J Am Acad Dermatol 2003 Apr;48(4):517-20 Abstract quote BACKGROUND: The coexistence of granuloma annulare (GA) and autoimmune thyroiditis (AT) has been sporadically observed in female patients, but the significance of this rarely reported association remains uncertain. OBJECTIVE: To investigate for the first time the frequency and type of thyroid disease in adult women with localized granuloma annulare (LGA) compared with a matched control group. METHODS: Twenty-four adult women with histology-proven LGA and a control group of 100 age-matched female patients with other unrelated cutaneous diseases were screened for thyroid disease in a tertiary teaching hospital in northern Spain. Laboratory evaluation included routine hematologic and chemistry analysis, antinuclear antibody, rheumatoid factor, thyroid function test (sensitive thyroid-stimulating hormone [TSH]), thyroid autoantibody levels, and antibodies to thyroid peroxidase in all patients and controls. Thyroid hormones (free triiodothyroxine and free thyroxine) were measured when TSH value was abnormal. AT was defined as hypothyroidism (TSH value >5 mU/L) and in addition to elevated antithyroid antibodies or characteristic thyroid biopsy. The results were compared using Fisher's exact test. RESULTS: Statistical evaluation of the findings obtained in this study showed mainly that the frequency of AT was increased significantly in the group of adult women with LGA (3/24, 12%) compared with the matched control group (1/100) (Fisher's exact test: P =.022). CONCLUSION: Although little can be inferred from a single investigation, the results of this pilot study indicate an association between LGA and AT in adult female patients, supporting the theory that at least a subset of GA belongs to the spectrum of autoimmune diseases.
LYMPHOCYTIC COLITIS
Increased colonic intraepithelial lymphocytes in patients with Hashimoto's thyroiditis. Cindoruk M, Tuncer C, Dursun A, Yetkin I, Karakan T, Cakir N, Soykan I. Department of Gastroenterology, Gazi University Medical School, Ankara, Turkey.	J Clin Gastroenterol 2002 Mar;34(3):237-9 Abstract quote BACKGROUND: Hashimoto's thyroiditis is an autoimmune thyroid disorder. Lymphocytic colitis and collagenous colitis are characterized by diarrhea with normal endoscopic findings. Autoimmune disorders are common in Hashimoto's thyroiditis and lymphocytic colitis. The aim of this study was to investigate the incidence of lymphocytic colitis in patients with Hashimoto's thyroiditis. STUDY: Fifty patients with well-documented Hashimoto's thyroiditis were included. Twenty patients with nonulcer dyspepsia served as a control group. Five of 50 patients with Hashimoto's thyroiditis reported intermittent diarrhea, whereas no patients had diarrhea in the control group. All patients and the control group underwent total colonoscopy, and multiple colonoscopic biopsies were performed. RESULTS: We found that 40% (20 of 50) of Patients with Hashimoto's thyroiditis had histologic findings consistent with lymphocytic colitis, and one patient in the control group had lymphocytic colitis (p < 0.01). The mean number of intraepithelial lymphocytes was 34.4/100 epithelial cells in these 20 patients, whereas the mean number of intraepithelial lymphocytes was 12.3/100 epithelial cells in the other 30 patients with Hashimoto's thyroiditis (p < 0.05). CONCLUSIONS: There was a higher incidence of histologic findings of lymphocytic colitis in patients with Hashimoto's thyroiditis, although most of the patients were clinically asymptomatic. This finding suggests that lymphocytic colitis may have an asymptomatic clinical course and should encourage further clinical investigations to better anticipate the relationship between autoimmune disorders.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA
Sclerosing mucoepidermoid thyroid carcinoma with eosinophilia. A distinctive low-grade malignancy arising from the metaplastic follicles of Hashimoto's thyroiditis. Chan JK, Albores-Saavedra J, Battifora H, Carcangiu ML, Rosai J. Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.	Am J Surg Pathol 1991 May;15(5):438-48 Abstract quote Eight cases of a distinctive low-grade carcinoma of the thyroid gland occurring in a background of Hashimoto's thyroiditis are reported. The patients were women presenting with a painless thyroid mass. Grossly, the tumors were white, homogeneous, firm, and usually ill defined. Histologically, strands and small nests of squamoid tumor cells exhibiting mild to moderate nuclear pleomorphism, distinct nucleoli, and pale cytoplasm infiltrated an abundant, dense fibrohyaline stroma. Foci of definite squamous differentiation and small pools of mucin were often found within the tumor nests. The neoplastic cells were immunoreactive for cytokeratin, but not for thyroglobulin or calcitonin. The stroma and many of the tumor islands were infiltrated by eosinophils in all cases. Extrathyroidal extension occurred in five cases and lymph node metastases in one. This tumor seems to arise from the benign squamous nests sometimes associated with mucin deposition found in Hashimoto's thyroiditis and thought to be the result of metaplastic changes of the follicular epithelium. It shares several morphologic features with cases previously reported as mucoepidermoid carcinoma of the thyroid, but it differs from them in other respects. The differential diagnosis includes undifferentiated/squamous cell carcinoma, intrathyroidal thymic carcinoma, and direct extension or metastasis of carcinoma from other organs.
Sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid: report of two patients, one with distant metastasis, and review of the literature. Sim SJ, Ro JY, Ordonez NG, Cleary KR, Ayala AG. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.	Hum Pathol 1997 Sep;28(9):1091-6 Abstract quote Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a recently recognized malignant neoplasm of the thyroid gland. Two additional cases of this condition which occurred in a 70-year-old woman and a 69-year-old woman are presented. The case of the 70-year-old woman (patient 1) is the first report of distant metastasis, besides lymph node metastasis, for this type of tumor. The patient initially presented with a thyroid mass, and the thyroid gland with surrounding cervical lymph nodes was removed. Because of focal keratin "pearl" formation, the tumor was misinterpreted as a metastatic squamous cell carcinoma to the thyroid. Approximately 4 years later, the patient developed a left supraclavicular mass and lung densities. A pathological fracture of the right humeral head followed, and the left supraclavicular mass recurred along with newly developed subcutaneous nodules on the chest wall and arm. Open lung and bone biopsies revealed metastatic SMECE, which was morphologically identical to that of the thyroid mass. The 69-year-old woman (patient 2) had, in 1983, undergone thyroidectomy with left radical neck dissection; this had been diagnosed as follicular carcinoma of the thyroid with lymph node involvement. After multiple isolated lymph nodes metastases, the patient developed locally extensive, recurrent tumor that showed microscopic features of SMECE. Review of the previous thyroid tumor and lymph nodes revealed the same type of histology. To our knowledge, only a single report containing eight cases of this distinctive carcinoma of the thyroid has been published. Herein we describe characteristic morphological features of two additional cases of this rare malignancy, one with distant metastasis, and we review the related literature.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

PATHOGENESIS	CHARACTERIZATION
NITRIC OXIDE SYNTHASE
Up-regulation of cyclooxygenase-2 expression in lymphocytic thyroiditis and thyroid tumors: significant correlation with inducible nitric oxide synthase. Nose F, Ichikawa T, Fujiwara M, Okayasu I. Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.	Am J Clin Pathol 2002 Apr;117(4):546-51 Abstract quote To cast light on relations of cyclooxygenase-2 (COX-2) expression to lymphocytic thyroiditis and thyroid tumorigenesis, protein levels were immunohistochemically assessed and compared with inducible nitric oxide synthase (iNOS) in a total of 181 cases: follicular adenoma, 23; well-differentiated papillary carcinoma, 85; poorly differentiated papillary carcinoma, 25; anaplastic carcinoma, 7; and follicular carcinoma, 41. In addition, 72 specimens of normal follicular epithelia and 36 of lymphocytic thyroiditis were used as control samples. Immunohistochemical results were confirmed in 2 cases each of normal thyroid, lymphocytic thyroiditis, and well-differentiated and poorly differentiated papillary carcinoma, by Western blotting assay. Stepwise increments in overexpression of COX-2 and iNOS were revealed in epithelial cells of lymphocytic thyroiditis, follicular adenoma, and papillary carcinoma; normal thyroid epithelium showed little expression. A significant positive correlation between the 2 enzymes was found with all cases. Enhanced expression of both COX-2 and iNOS suggests important roles in the inflammatory processes underlying lymphocytic thyroiditis and thyroid tumorigenesis.
RET/PTC
Prevalence of RET/PTC Rearrangements in Hashimoto's Thyroiditis and Papillary Thyroid Carcinomas. Nikiforova MN, Caudill CM, Biddinger P, Nikiforov YE. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA.	Int J Surg Pathol 2002 Jan;10(1):15-22 Abstract quote The relationship between Hashimoto's thyroiditis (HT) and follicular cell-derived thyroid cancer remains unclear. Recently, 2 studies reported a 95% prevalence of RET/PTC rearrangements in histologically benign tissue affected by HT, suggesting that multiple occult tumors exist in HT patients with high frequency. We tested the prevalence of RET/PTC rearrangements in 26 HT, in 6 papillary carcinomas arising in the background of HT, and in 27 papillary carcinomas not associated with HT. We detected no RET/PTC rearrangements in HT or papillary carcinomas arising in the background of HT, in contrast to a 33% prevalence among papillary carcinomas not associated with HT. However, the expression of wild-type RET was found in more than half of papillary carcinomas. These results suggest that, if the association between HT and thyroid cancer exists, its molecular basis is different from RET/PTC rearrangement.

HISTOPATHOLOGICAL VARIANTS	CHARACTERIZATION
GENERAL	Hum Pathol 1982;22:980 Lymphoplasmacytic infiltrate with secondary germinal centers and variable fibrosis. Thyroid follicles are usually small and may be atrophic. Oncocytic, clear cell, and squamous metaplasia is common within the follicular cells.
Classification of Chronic Lymphocytic Thyroiditis	Classic Hashimoto's thyroiditis
Mixed	Lesser inflammatory infiltrate with minimal fibrosis May be eu-, hypo-, or hyper-thyroid
Hyperplastic	Glandular hyperplasia with small lymphocytic reaction Usually hyperthyroid
Focal	Focal lymphocytic reaction Usually normothyroid (euthyroid)
VARIANTS
FIBROSING	There is an interesting variant known as a fibrosing variant, occurring in 10% of cases. It is more common in elderly individuals who have goiters and hypothyroidism Dense keloid-like fibrosis with severe follicular atrophy, and squamous metaplasia of the follicular epithelium.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
TREATMENT
SURGERY
Surgical treatment of Hashimoto's thyroiditis. Personal experience. Carli AF, Lottini M, Testa M, Neri A.	Minerva Chir 2002 Apr;57(2):117-22 Abstract quote BACKGROUND: To report personal experience in the surgical treatment of Hashimoto's thyroiditis. METHODS. Eight patients (7 females, 1 male, mean age 48 years old) referred to our Institu-tion with diagnosis of Hashimoto's thyroiditis have been studied. All patients were evaluated by determination of serum thyroid hormones and of anti-thyreoglobulin and anti-microsomal antibodies; ultrasound and scintigraphic scans of the gland were performed in all cases and a cytological examination of fine needle aspiration (FNAC) of the nodules was evaluated. Diagnosis of Hashimoto's thyroiditis was suspected on the basis of clinical and laboratory data and was confirmed by cytology and histology on surgical specimens. Preoperative FNAC showed a Hashimoto's thyroiditis with thyroid differentiated carcinoma in 3 cases (37.5%), Hashimoto's thyroiditis in 1 case and chronic thyroiditis in 4 cases (50%). Seven patients underwent surgery, while 1 patient received a medical treatment; we performed 6 total thyroidectomies and 1 hemithyroidectomy. Histology on surgical specimens confirmed the diagnosis of Hashimoto's thyroiditis in all cases; in 3 patients an associated papillary thyroid carcinoma was found. RESULTS: Postoperative mortality was absent; no major postoperative complications (laryngeal nerve paralisis or permanent hypocalcemia) were recorded. Only 2 mild transient hypocalcemias have been observed. CONCLUSIONS: Total thyroidectomy is the technique of choice in surgical treatment of Hashimoto's thyroiditis, a self-immune pathology which involves the whole gland and has a high correlation with differentiated thyroid carcinoma (37.5%). Total thyroidectomy warrants a radical and definitive control of the disease, without risk of relapse, with a low incidence of major complications, in experienced hands, and anyway lower than the morbility due to reinterventions.