Past Surgical History Unremarkable. case study [chemistry histology]

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1 case study [chemistry histology] Chronic Cough in an Older Female Ellen Sigauke, MD, Thompson T. Kamba, MD, Monte S. Willis, MD, PhD Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX DOI: /LK7FD90VKCWXNCGF Patient 62-year-old African-American woman. Chief Complaint Chronic cough, shortness of breath, chest discomfort, weight loss, and malaise (vague feeling of bodily discomfort). History of Present Illness Patient reported having a chronic cough associated with chest discomfort. She denied any fever or night sweats. Past Medical History Hypertension and gastroesophageal reflux disease (GERD). Past Surgical History Unremarkable. Drug History Patient was currently taking Losartan (an angiotensin II receptor antagonist, 50 mg every day) for hypertension and Rabeprazole (a proton pump inhibitor, 20 mg every day) for GERD. Family/Social History The patient s family history was unknown. She denied use of any tobacco products, illicit drugs, or excessive alcohol. The patient denied any significant travel history, personal history of tuberculosis, or contact with others with tuberculosis. Physical Examination Vital signs: temperature, 36.5ºC; respiratory rate, 20 bpm; heart rate, 93 bpm; blood pressure, 160/96 mm Hg. Physical examination was unremarkable except for raised reddishbrown papular skin lesions located on her elbows, knees, and extensor surfaces of the lower legs bilaterally consistent with erythema nodosum. 99

2 Principal Laboratory Results [T1] Results of Diagnostic Procedures and Additional Tests A chest X-ray revealed hilar prominence. A chest CT revealed adenopathy with multiple pulmonary nodules (too many to count) [I1] and a right pleural effusion. A skin biopsy demonstrated unremarkable epidermis with nodules of epithelioid histiocytes surrounded by lymphocytes in the dermis consistent with a non-necrotizing granulomatous dermatitis [I2]. Staining of the skin biopsy for acid-fast organisms (eg, Mycobacteria spp.) with Fite s acid-fast stain and for fungal elements with Gomori s methenamine silver (GMS) stain was negative. Questions: 1. What is the patient s most striking clinical and laboratory result(s)? 2. How do you explain this patient s most striking laboratory result(s)? 3. What condition(s) does this patient s laboratory and other findings suggest? 4. What are the clinical manifestations of this disease? 5. How is the clinical staging of this patient s disease performed and what is its relationship to long-term survival? 6. What is the most appropriate treatment for this patient? Possible Answers: 1. Chronic cough, skin lesions, negative tuberculosis contacts, increased serum total protein with normal albumin concentration, elevated serum calcium, hilar prominence on Principal Laboratory Findings Test (Serum) Patient s Result Normal Reference Range Total protein g/dl Albumin g/dl Sodium mmol/l Potassium mmol/l Chloride mmol/l Bicarbonate mmol/l BUN mg/dl Creatinine mg/dl Calcium mg/dl Phosphorus mg/dl ALP U/L AST U/L ALT U/L Amylase U/L Lipase U/L T1 BUN, blood urea nitrogen; ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase the chest radiograph, adenopathy with multiple pulmonary nodules on chest CT, non-necrotizing granulomas on skin biopsy with negative mycobacterial and fungal stains, and the presence of erythema nodosum. 2. Chronic cough. The causes of chronic cough are: 1) environmental irritants (eg, cigarette smoke, pollutants, dust, lack of humidity); 2) lower respiratory tract problems [eg, lung cancer, asthma, chronic obstructive pulmonary disease (COPD), pneumonitis, bronchiectasis]; 3) upper respiratory problems [eg, chronic rhinitis, chronic sinusitis, disease of the external auditory canal, pharyngitis, therapy with A B 100 [I1] A chest CT revealed multiple bilateral pulmonary nodules (arrows) on multiple sections (panels A and B) and a right pleural effusion (not shown).

3 A B [I2] Histological section from a punch biopsy of an affected area of the patient s skin. H&E stained section (40x magnification) demonstrates an unremarkable epidermis (arrows in panel A) and specific nodules (from panel A circle) of epithelioid histiocytes (numbered 1 to 3 in panel B; 100x magnification) with surrounding lymphocytes without any necrosis present. angiotensin converting enzyme (ACE) inhibitors]; and 4) extrinsic compressive lesions to the upper or lower respiratory tract due to things such as adenopathy (as seen in granulomatous diseases such as tuberculosis, sarcoidosis, and lymphoma), malignancy, aortic aneurysm, and reflux esophagitis. Increased serum total protein with normal albumin concentration. This combination of findings indicates increased serum globulin concentration due to monoclonal or polyclonal hypergammaglobulinemia. Monoclonal hypergammaglobulinemia is most often associated with multiple myeloma and other plasma cell dyscrasias, while polyclonal hypergammaglobulinemia can be due to a variety of causes including bacterial infections and sarcoidosis. Hypercalcemia. There are many different diseases that can lead to hypercalcemia. In symptomatic patients where hypercalcemia is detected by routine screening, primary hyperparathyroidism is the most common cause. In hospitalized patients, malignancy is a common cause of hypercalcemia. Other, less common causes of hypercalcemia include thyrotoxicosis, immobilization, granulomatous disease (eg, sarcoidosis), increased bone turnover (eg, Paget s disease), as well as acute renal failure seen with rhabdomyolysis. Hypercalcemia occurs in less than 10% of patients with sarcoidosis and is thought to be caused by elevated 1,25-dihydroxyvitamin D (calcitriol) produced by macrophages within granulomas (as seen in I2B). Hypercalciuria occurs with a higher estimated frequency of 30% to 40%. 1 Increased calcitriol leads to increased calcium absorption from the intestine leading to hypercalcemia. Hilar adenopathy. A chest radiograph in patients with sarcoidosis can reveal hilar adenopathy in the lungs. It is important to note that hilar adenopathy can be due to a myriad of other disorders including tuberculosis and lymphomas which could be fatal if missed. Enlarged lymph nodes in the hilar region of the lungs can be seen in bronchogenic carcinoma (lung cancer), coccidiomycosis, histoplasmosis, lymphoma, sarcoidosis, and tuberculosis. It is therefore important to rigorously rule out such conditions when considering the diagnosis of sarcoidosis. Radionuclide scanning with Gallium-67 can be useful in monitoring the disease process. 2 Pulmonary nodules. Pulmonary nodules may be caused by neoplastic, granulomatous, vascular, and cystic processes and are formed due to the displacement of normal aerated lung parenchyma. Generally, no symptoms are seen unless the airway is obstructed, the pleura invaded, or nerves or blood vessels become involved. Non-caseating granulomas on skin biopsy. Non-caseating granulomas on skin biopsy are generally well formed and consist of a collection of epithelioid histiocytes which are surrounded by variable numbers of lymphocytes. Multinucleated giant cells can be present in the granulomas. Non-caseating granulomas are also seen in hypersensitivity pneumonitis, where they are not as well-formed and discrete as those found in sarcoidosis. Erythema nodosum. Erythema nodosum is an inflammatory reaction of the subcutaneous fat that represents a hypersensitivity response. Multiple nodules, 1 to 5 cm in size develop usually over the pre-tibial areas bilaterally. These lesions subsequently involute and lead to yellow and purple bruises without ulceration. It is believed that hemodynamic considerations are the reason for the localization to the lower legs. Several factors have been associated with erythema nodosum including drugs (oral contraceptives), pregnancy, inflammatory bowel disease, sarcoidosis, streptococcal infection, Yersinia spp. infection, enterocolitis, deep fungal infections, and tuberculosis. Treatment of the underlying disease resolves erythema nodosum; however, if the cause is not identified, symptomatic therapy using non-steroidal anti-inflammatory drugs 101

4 102 (NSAIDs), aspirin, potassium iodide, or short courses of systemic steroids can be useful. 3. Most likely diagnosis: Sarcoidosis. Note that sarcoidosis was among the different causes of 6 out of the 7 most striking clinical or radiological findings exhibited by this patient. The diagnosis of sarcoidosis is made by the findings of erythema nodosum, hilar adenopathy with a negative culture or serology for histoplasmosis, or manifestations of organspecific disease with non-caseating granulomas [T2]. The most common sites of diagnostic biopsies in patients with sarcoidosis are the skin, pulmonary parenchyma, and intrathoracic lymph nodes. This patient exhibited increased total protein (globulins), hypercalcemia, hilar adenopathy [I1], non-caseating granulomas on skin biopsy [I2], and erythema nodosum. Hypergammaglobulinemia can be found in patients with multiple myeloma or sarcoidois; however, multiple myeloma is rarely associated with sarcoidosis, and sarcoidosis precedes the development of multiple myeloma in most cases. 3 Motoyama and colleagues reported a case of symptomatic hypercalcemia presenting as the initial manifestation of sarcoid without any other organ involvement. 4 Sarcoidosis has also been associated with Sweet s syndrome [fever, leukocytosis (neutrophilia), and a painful, erythematous plaque-like skin lesion] which has recently been described and reviewed. 5 While Sweet s syndrome is commonly associated with hematological malignancies, the diagnosis of acute sarcoidosis was found to be more common in this study. 5 Increased levels of angiotensin converting enzymes (ACE) are beneficial in following disease progression in sarcoidosis. An elevated CD4/CD8 ratio in a bronchoalveolar lavage specimen may be helpful in pointing towards a granulomatous disease; however, it is not diagnostic of sarcoidosis. In fact, the CD4/CD8 ratio has been found to be highly variable in proven sarcoidosis cases. 6 Other nonspecific laboratory findings in patients with sarcoidosis include, but are not limited to, leukopenia, an elevated erythrocyte sedimentation rate, and an elevated alkaline phosphatase. A biopsy that demonstrates the presence of noncaseating granulomas and giant cells is important in making the diagnosis of sarcoidosis; however, these findings are nonspecific. Moreover, necrotizing sarcoid granulomas can occur but are a rarity. 7 In the past, a sarcoid spleen-derived reagent was used in the Kveim-Siltzbach test (KST), to elicit a sarcoid-specific, granulomatous, cutaneous reaction in order to diagnose patients with sarcoidosis. However, it is no longer widely used. Sarcoidosis is a chronic, idiopathic granulomatous multisystem disorder, characterized by non-caseating granulomas and an accumulation of T-lymphocytes and mononuclear phagocytes. In the United States, the disease is more common in African-Americans than in Caucasians and in females than in males. However, approximately 80% of people with sarcoidosis worldwide are Caucasian. Sarcoidosis can affect any age group, although it is most commonly found in persons 20 Criteria for Diagnosing Sarcoidosis * T2 1. Erythema nodosum and hilar adenopathy with or without arthalgia/polyarthritis/periarthritis. No histoplasmosis determined by appropriate cultures/serology Or 2. Biopsy-proven manifestations of organ-specific non-caseating granulomas in any of the following locations: meninges lung parenchyma paratracheal or hilar lymph node bone synovium skeletal muscle superficial lymph node skin lesion * Source: Ruddy: Kelley s Textbook of Rheumatology, 6th ed., Copyright 2001 W. B. Saunders Company, Philadelphia. to 29 years of age. 8 Approximately 75% of people with sarcoidosis are under the age of 30 at the time of presentation. Although no specific etiological agent has been determined, multiple causes have been postulated. Its association with individuals with class I HLA-A1, B8, and class II HLA-DR3 antigens suggests a genetic etiology. Moreover, familial clusters of the disease have been identified. Support for an immune etiology of sarcoidosis comes from the presence of autoantibodies, uveitis (inflammation of the uvea in the eye commonly involving the sclera, cornea, and retina), erythema nodosum (inflammation of the subcutaneous fat), and its response to immunomodulating drugs (eg, corticosteroids) in patients with sarcoidosis. The presence of granulomas in sarcoidosis, which are found also in environmental and occupational diseases (eg, berylliosis, due to exposure to beryllium, which produces a histologic and clinical presentation similar to sarcoidosis), supports the hypothesis that environmental or occupational exposure may be the cause. Other postulated etiologies include infection with organisms such as mycobacteria, Propionibacteria acnes, Tropherema whippelii, the Epstein-Barr virus, and other herpes-like viruses. 9 While definitive evidence for the cause of sarcoidosis is lacking, information regarding the pathogenesis of the disease has been growing. Macrophages that take up and process antigens are thought to be central to the disease process by triggering an expansion of CD4+ T-helper cells with a TH1 phenotype, characterized by interleukin-2 (IL-2) and interferon-gamma (IFN-γ) production. The IL-2 causes the proliferation of additional CD4 cells which in turn elaborate more cytokines that recruit macrophages and lead to the formation of a granuloma. Lymphocytes and macrophages release many cytokines which amplify the inflammatory process and the potential to induce fibrosis. While B-lymphocytes do not appear to play a major role in the etiology of sarcoidosis, they are affected by mediators released from the T-lymphocytes which triggers the polyclonal hypergammaglobulinemia often observed in patients with sarcoidosis. Patients with sarcoidosis may be asymptomatic or can present with non-specific symptoms such as fever and weight loss; however, most have respiratory symptoms. In addition, the disease can be acute or chronic. The acute form results in

5 Lofgren s syndrome or Heerfordt-Waldenström syndrome. Lofgren s syndrome is seen in 10% to 20% of patients at presentation and consists of the findings: 1) erythema nodosum; 2) bilateral hilar adenopathy on chest radiograph; and, 3) the presence (classically) of joint pain and/or fevers. The Heerfordt- Waldenström syndrome presents as: 1) fever; 2) parotid enlargement; 3) anterior uveitis; and, 4) facial nerve palsy. These syndromes are generally self-limiting. The chronic form is insidious and develops over several months and can include non-specific features that include, but are not limited to, hypopituitarism, diabetes insipidus, lupus pernio (a disfiguring skin lesion of the face), nasal mucosa lesions, lymphadenopathy, salivary gland involvement, hepatomegaly, splenomegaly, cor pulmonale, hypercalciuria, renal stones, bone cysts, chronic ulcers, erythema nodosum, transient vesicular eruptions on the fingers, and skin plaques. Old scars and tatoos many times are infiltrated with granulomas. 4. The clinical manifestations of this disease are variable and almost any organ system can be affected. The respiratory system is most commonly affected (90%) with intrathoracic involvement seen on a chest radiograph. Patients can develop extrathoracic disease with or without intrathoracic involvement and extrathoracic disease may be the predominant clinical picture in some cases. Patients are asymptomatic 30% to 60% of the time at presentation and the disease is identified because of chest radiographic findings. Respiratory disease. Intrathoracic lymph node involvement and parenchymal lung disease are the most common ways in which sarcoidosis affects the respiratory system with both hilar and mediastinal lymph nodes being affected. Dyspnea and a non-productive cough are the primary symptoms that occur. Skin disease. Cutaneous manifestations result from granuloma formation which affects 15% to 20% of patients. The lesions are variable and include papules, plaques, nodules, and infiltration of old scars. Lupus pernio is a disfiguring lesion that affects the ears, cheeks, and nose. Erythema nodosum commonly occurs in patients with bilateral adenopathy (Lofgren s syndrome). Eye disease. Ocular disease takes on several forms including uveitis, conjunctival involvement, and papilledema. The most common manifestation is uveitis with an accompanying acute onset of photophobia and ocular discomfort. In Heerfordt s syndrome, uveitis accompanies parotid gland enlargement, fever, and facial palsy. Cardiac disease. The most common cardiac involvement due to sarcoidosis manifests as conduction defects (heart block), arrhythmias, and heart failure. Neurologic disease. Any nerve can be involved; however, the most common form of neurologic disease is unilateral facial nerve palsy. Clinical manifestations of neurologic disease include seizures, meningitis, peripheral neuropathy, as well as psychiatric symptoms. Liver. Symptoms related to liver involvement are rare and are usually limited to abnormal hepatic enzymes. Lymph nodes. In addition to the intrathoracic involvement, peripheral lymph nodes may be enlarged due to infiltration by Characteristics of the Clinical Stages of Sarcoidosis* Stage Hilar Parenchymal Incidence, % Percentage Adenopathy Disease of Cases Present Present that Resolve 0 no no <10 n.a. 1 yes no yes yes no yes <20 4 no yes <20 T3 * Source: Goldman: Cecil Textbook of Medicine, 21st ed, Copyright 2000 W. B. Saunders Company, Philadelphia. Progression to parenchymal disease occurs in less than 10% of Stage 1 patients. With fibrosis. n.a., not applicable. granulomas. Biochemical changes. Elevated calcium levels and ACE activity can occur in patients with sarcoidosis. Elevated ACE activity occurs in 40% to 90% of cases and is thought to be caused by the production of this enzyme by epithelioid cells and macrophages found in granulomas. Measurement of ACE levels, however, lacks diagnostic specificity and does not reflect prognosis accurately, and is therefore rarely used in the management and diagnosis of patients with sarcoidosis. 5. Sarcoidosis staging is based primarily on radiographic findings. Four stages of sarcoidosis have been described [T3]. In stage 0, systemic involvement with a normal chest radiograph is seen. Less than 10% of patients present in this stage of disease. Stage 1 disease is characterized by bilateral hilar lymphadenopathy with or without paratracheal adenopathy. Approximately 50% of patients present with this stage of disease, and are usually asymptomatic or may have non-respiratory symptoms. Sarcoidosis resolves in 65% of these patients. Stage 2 disease presents with bilateral hilar adenopathy in addition to diffuse pulmonary infiltrates (with or without pulmonary nodules). Approximately 30% of patients present with this stage of disease and 20% to 50% of these patients have resolution of their disease. The clinical findings in this stage appear mild in relation to the chest findings. Advanced fibrosis, honeycombing, cysts, bullae, and emphysematous changes are found in Stages 3 and 4 of disease. Other findings include, atelectasis, nodular cavitation, calcifications, and pleural thickening and effusions. 2 Few patients present with these stages of disease (10% to 15%) and <20% of these patients have resolution of their disease. 6. If left untreated, 30% to 50% of patients with sarcoidosis have a spontaneous remission within 3 years, 30% progress to a more serious stage of disease, and 20% to 30% remain stable over a 5 to 10 year period. 2 Reccurrence of disease depends on the initial stage of the patient s disease [T3]. Corticosteroids remain the mainstay of treatment for sarcoidosis, although other therapeutic modalities have been reported. Katoh and colleagues reported a case of a 62-year-old female with cutaneous sarcoidosis who responded to topical tacrolimus after failing to respond to topical and systemic corticosteroids. 10 Thalidomide has also reportedly 103

6 been beneficial in improving skin lesions in patients with sarcoidosis. 11 Patient s treatment and course The patient was started on corticosteroid therapy (fluocinonide ointment) and an antibiotic (bacitracin ointment) and referred for follow-up to the pulmonary and dermatology services. Additionally, she was referred to the ophthalmology service for evaluation of possible eye complications of her disease. Keywords: sarcoidosis, hilar prominence, adenopathy 1. Gardner DG. Hypercalcemia and sarcoidosis-another piece of the puzzle falls into place. Am J Med. 2001;110: Murray JF, Nadel JA, Mason RJ, et al. Textbook of Respiratory Medicine, 3rd ed. Philadelphia: W.B. Saunders Company. 2000;2: Sen F, Mann KP, Medeiros LJ. Multiple myeloma in association with sarcoidosis. Arch Pathol Lab Med. 2002;126: Motoyama K, Inaba M, Emoto M, et al. Sarcoidosis initially manifesting as asymptomatic hypercalcemia with the absence of organic involvement. Intern Med. 2002;41: Stuveling EM. The association of Sweet s syndrome with sarcoidosis. Netherlands J Med. 2001;59: Kantrow SP, Meyer KC, Kidd P, et al. The CD4/CD8 ratio in BAL fluid is highly variable in sarcoidosis. Eur Respir J. 1997;10: Gal AA, Koss MN. The pathology of sarcoidosis. Curr Opin Pulm Med. 2002;8: Yutaka H, Sumiko S, Norikazu Y. Epidemiology of sarcoidosis: New frontiers to explore. Curr Opin Pulm Med. 2002;8: David MR, Edward CS. What causes sarcoidosis? Curr Opin Pulm Med. 2002;8: Katoh N, Mihara H, Yasuno H. Cutaneous sarcoidosis successfully treated with topical tacrolimus. Br J Dermatol. 2002;147: Baughman RP, Judson MA, Teirstein AS, et al. Thalidomide for chronic sarcoidosis. Chest. 2002;122: