Amyloidosis of the Head and Neck: a Clinicopathological Study of Cases with Long-Term Follow-Up

Letter to the Editor

Amyloidosis of the head and neck: a clinicopathological study of cases with long-term follow-up

Wioletta Pietruszewska 1, Małgorzata Wągrowska-Danilewicz 2, Janusz Klatka 3

1Department of Otolaryngology and Laryngological Oncology, Medical University Corresponding author: of Lodz, Poland Wioletta Pietruszewska 2Department of Nephropathology, Medical University of Lodz, Poland Department of Otolaryngology 3Department of Otolaryngology and Laryngological Oncology, Medical University and Laryngological Oncology of Lublin, Poland Medical University of Lodz 22 Kopcinskiego St Submitted: 12 February 2012 90-153 Lodz, Poland Accepted: 17 June 2012 Phone: +48 602 225 721 E-mail: wioletta.pietruszewska Arch Med Sci 2014; 10, 4: 846–852 @umed.lodz.pl DOI: 10.5114/aoms.2013.39206 Copyright © 2014 Termedia & Banach

Extracellular deposits of insoluble proteinaceous material giving a starch- like reaction when treated with iodine and sulphuric acid and accumulat - ing in tissue was for the first time described by Rokitansky in 1842 [1]. It was not until 1851 that Virchow applied the term “amyloidosis” to describe this deposition [2]. An amorphous substance called amyloid (insoluble fib - ril-forming protein) is deposited in extracellular spaces of organs and tis - sues. Amyloid deposits, under the electron microscope, appear as non- branching fibrils with a cross-linked, β-pleated sheet conformation. They are eosinophilic after haematoxylin–eosin staining and display apple-green birefringence with polarized light when stained with Congo red. Chronic inflammations of bacterial or non-bacterial origin and immunological immune-competent neoplasm cells are examples of factors that induce amyloid fibril biosynthesis. The organs and tissues where amyloid deposits occur become stiff and plastic, having a hyaline-like appearance that leads to a loss of previous function [3]. Amyloidosis is probably caused by rearrangement in the immune system, though its pathogenesis is not still known thoroughly. It is a heterogeneous group of diseases having misfolding of extracellular protein as a common etiological factor. Chronic inflammation with extensive tissue destruction, malignant proliferation of plasmocytes and autoimmune diseases promote expansion of amyloidosis. Various clinical types of amyloidosis have an impact on its natural course, therapy and prognosis. Amyloidosis can be divided into various biochemical forms depending on amyloid deposit type: NH 2-terminal immunoglobulin fragments or their light chains (AL protein); AA protein originated from serum amyloid A (SAA); transthyretin in senile amyloidosis; amino acid sequences of insulin, glutathione, calcitonin, β2- microglobulin in chronic haemodialysed patients, APP protein in Alzheimer disease patients, amylin, natriuretic peptide are exemplary proteins, which can accumulate in the tissue forming amyloid [4–7]. Amyloidosis can be clinically divided into localized or systemic with extremely different clinical course. Kidneys, spleen, liver and heart, but also adrenals, pituitary gland, thyroid and alimentary tract are the organs most frequently affected by systemic amyloidosis. The most significantly involved organ systems are heart and kidneys. Extracellular deposition of amyloid leads to their failure, which constitutes the two leading causes of death of patients with systemic amyloidosis. Wioletta Pietruszewska, Małgorzata Wągrowska-Danilewicz, Janusz Klatka

There are 25 described biochemical forms of criteria: no detected diseases possibly underlying amyloidosis, from among which three types are the the amyloidosis and deposits of amyloid with evi - commonest in clinical practice [3, 8]. The first of dence of AL type in at least one biopsy site [10]. them is AL-amyloidosis (light chain) – most often In all cases haematoxylin-eosin and Congo red primary/idiopathic or multiple myeloma-associat - stains positive for apple-green birefringence under ed. NH 2-terminal fragment or whole immunoglob - polarized light were performed to confirm the diag - ulin light chains, derived from a monoclonal popu - nosis. The examination was completed with immu- lation of bone marrow cells, are incorrectly modified nohistochemistry with antibodies against serum and produce amyloid deposits. The second type of amyloid A and κ and λ light chains of immuno- amyloidosis – the secondary, acquired or reactive glob ulins (DakoCytomation). The visualization one – is characterized by a defect of precursor pro - of the immunological reactions was performed tein transformation (acute phase protein – serum using the immunoperoxidase method with LSAB/ amyloid A (SAA)). NH 2-terminal, unique sequence Universal Kit (DakoCytomation). As a chromogen of non-immunoglobulin protein coexisting with diaminobenzidine (DAB) (DakoCytomation) was C-reactive protein (CRP) and tumor necrosis factor- used. α (TNF- α) accelerates the deposition of amyloid in Multiple myeloma was excluded by serum the tissue significantly. Increased serum levels of M-protein lower than 3.0 g/dl, plasma cells less these factors are usually connected with inflam - than 10% of the total number of nucleated cells in matory conditions – hence the name of this type the bone marrow and no evidence of osteolytic of amyloidosis, secondary to infections. It occurs lesions according to criteria of the International during infectious diseases (such as tuberculosis, Myeloma Working Group [11]. bone marrow inflammation, leprosy) or inflamma - The patients included 3 men and 4 women aged tory states (rheumatoid arthritis, Crohn disease, from 41 to 64 at an average of 48.7 at presentation inflammatory bowel disease, connective tissue dis - (median 44, SD 9.03). The location of the amyloid order). Secondary amyloidosis shows a predilection deposits were as follows: amyloidosis was revealed for the spleen, liver, kidneys, lymph nodes and in the tongue in two cases and similarly in the phar - adrenals. Extensive changes in the vascular system ynx; single cases of amyloid deposits were located are also possible [4, 9]. The third type of amyloido - in the larynx, the palatine tonsil and the sub - sis (hereditary) is quite rare and runs in families, mandibular gland in this group of patients. and is not connected with other diseases. Particu - The initial clinical presentation correlated lar kinds of neuropathy and cardiomyopathy (neu - with localization of amyloid tumour in our patients ropathic form) are typical for this type of amyloi - (Table I). dosis. Autosomal recessive familial Mediterranean In all cases there were no other laryngological, fever is the most common condition in this type. rhinological or otological symptoms apart from the Another is a group of autosomal dominant familial ones mentioned above. Also the patients had no amyloid polyneuropathies [8, 9]. symptoms referable to the musculoskeletal system Amyloidosis affecting the head and neck occurs with no weight loss, abdominal or cardiac discom - mostly as a localized formation although it is very fort, with good appetite. All the patients had no rare. Therefore often it is diagnosed after surgical radiation or major trauma to their involved site of treatment on the basis on histopathological find - amyloid tumour. All other laboratory findings, ings. including chest X-ray examination, abdominal ultra - We present the clinical and histopathological sound, electro- and echocardiogram, complete blood properties of 7 cases of head and neck amyloido - cell count, liver and renal function tests, serum and sis with a long follow-up. urine protein electrophoresis were normal. Post - Seven cases of localized amyloidosis in the head operative healing was uneventful in each case. No and neck region were selected from the files of the lymphoproliferative disorder was detected. In a long Department of Otolaryngology, Medical University observation no recurrences were detected in that of Lodz, and the Department of Otolaryngology, group of patients (Table I). Medical University of Lublin, from 1996 to 2006, Only in patient 7 did further studies confirm sys - that had clinical follow-up available. The following temic amyloidosis. The diagnostic process started clinical information was reviewed: symptoms at with taking an open biopsy from the tongue and presentation, laboratory results, surgical patholo - then from the rectum to find out if it was a sys - gy, operative reports, regarding the development of temic disorder. Despite treatment (prednisone and systemic or multifocal disease, extent of disease, melphalan), the patient died from circulatory fail - serum or urine electrophoretic studies, bone mar - ure within 1 month after the diagnosis and the ini - row biopsy, the specific treatment modalities, cur - tial treatment. rent status of the disease and the patient. The diag - On the histological examination the amyloid nosis of localized amyloidosis was based on two was presented as extracellular, amorphous, eosi -

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Arch Med Sci 3 Wioletta Pietruszewska, Małgorzata Wągrowska-Danilewicz, Janusz Klatka nophilic material on haematoxylin and eosin stain - cytological atypia of the lymphoplasmacytic infil - ing (Figure 1). trate was not identified. It was dispersed throughout the lamina propria, Apple green birefringence was seen in each case, frequently presenting perivascular and periglan - when sections stained with Congo red were viewed dular deposition, especially in the submandibular in high intensity polarized light confirming the diag - gland. Sparse, mixed infiltration consisted of lym - nosis of amyloidosis (Figures 2 and 3). phocytes and mature plasma cells with occasion - Immunohistochemical staining for serum amy - ally foreign-body type multinuclear giant cells pres - loid A protein was negative, which indicated non- ent at the periphery of the deposits. Significant AA amyloid protein deposition. In each case the amyloid precursor proteins were immunoglobulin light-chain fragments indicating the nature of the amyloid deposits being monoclonal immunoglobu - lins that confirmed AL-amyloidosis. Lambda chain restriction was present in 6/7 patients whereas κ was found only in 1 patient with nodular amyloid deposition in the nasopharynx (Figure 4). An extensive search of systemic amyloidosis and multiple myeloma was performed in all patients. Tis - sue samples from rectum mucous membrane were taken and no amyloid deposits were found in 6/7 patients; only in one patient were the results from both places positive for amyloid deposits. The bone marrow biopsy in patient 7 was negative for myelo - ma. Electrophoretic separation of urine proteins did Figure 1. Deposition of amyloid from the tongue in not reveal the presence of Bence-Jones protein, case of systemic AL amyloidosis (H + E staining, mag - which excluded multiple myeloma in 7/7 patients. nification 100×)

Figure 2. Congo red staining without polarization Figure 3. Deposits of amyloid displaying characteris - demonstrating deposition of amyloid in the posteri - tic apple-green birefringence by polarized Ligot mi - or wall of pharynx tumour (magnification 100×) croscopy (Congo red stain, magnification 100×) A B

Figure 4. A – Positive λ light chain immunohistochemical staining of the amyloid deposit in the pharynx tissue (mag - nification 400×). B – Negative κ light chain immunohistochemical staining in the amyloid deposit in the pharynx tis - sue (magnification 400×)

4 Arch Med Sci Amyloidosis of the head and neck: a clinicopathological study of cases with long-term follow-up

Depending on clinical and pathological findings, loid deposits account for 0.2–1.5% of benign laryn - in 6 cases a form of localized AL amyloidosis was geal tumours [6]. Laryngeal amyloidosis, contrary confirmed (patients 1–6). Only in one case (patient to the one pertaining to the tongue, is rarely a com - 7) was the diagnosis of systemic amyloidosis with - ponent of a systemic disease [6, 8, 14, 17, 18]. Oth - out multiple myeloma established. er reported sites for localized amyloidosis of head All patients with localized amyloidosis were ini - and neck are the thyroid gland, parathyroid gland, tially treated with surgical excision of the amyloid eyelid, nasopharynx, paranasal sinus, gingiva, cer - mass. Although all of them had long clinical follow- vical lymph nodes, maxilla, skull base, nasal sep - up available (mean 7.16 years, median 6.5, range tum, external ear canal, Waldeyer’s ring, parotid 4–12, SD 3.37), they are still being regularly followed gland, and temporal bone [19]. However, they are for 2–3 months without any evidence of local recur - all rare. Nasopharyngeal amyloidosis, for example, rence. One remaining patient with systemic amy - has been reported in the literature to date, with the loidosis had an unfavourable outcome, which was presented case, only in 14 subjects [20]. The larynx mentioned above. The exact treatment and follow- is the most common site affected by localized amy - up data are summarized in Table I. loidosis [4, 8, 21, 22] although in our series only one Although in the head and neck region amyloid patient had laryngeal localized amyloidosis. With - deposition is a rare condition [4, 12], it can be rela - in the larynx the most common locations are true tively frequent in comparison to other organs. Pen - and false vocal cords, sub- and supraglottis and ner and Muller [8] reported that head and neck anterior commissure [13], as we revealed in our amyloidosis accounted for 19% of all amyloid cas - patient as well. Localized deposits of amyloid in es. The condition is most often diagnosed between head and neck usually create single, icicle-like for - the fourth and sixth decade of life but localized cas - mations with a smooth surface, imitating benign es occurred earlier than systemic [13]. We observed tumours of waxen consistency [8, 16, 17], which in it also in our group of patients with localized AL our patients was also reported. with an average age of 48.7 while the patient with The pathogenic mechanism of localized amyloi - systemic AL was 64 years old. dosis is still unclear. The biopsy of head and neck Clinically, amyloidosis can be divided into sys - localized amyloidosis, contrary to the systemic one, temic and localized. However, only 9% to 15% of demonstrates the presence of numerous plasma amyloidosis is of the localized type. There are no cells and giant cells of histiocytic origin. There is characteristic symptoms for amyloidosis in the some evidence that monoclonal plasma cells at this upper aerodigestive tract. Pain and asymmetry of location are probably responsible for producing the lesion are typical for palatine amyloidosis [14]. structurally abnormal immunoglobulins with cer - Patients with amyloidosis of the larynx complain tain amino acid residues occurring at the highly con - of hoarseness, gradually increasing dyspnoea, served region of the light chain. That could change haemoptysis and dysphagia [4, 15]. Patient 4, who the configuration of the protein and render them presented laryngeal amyloidosis, complained only particularly amyloidogenic, which results in local - of hoarseness. In most cases, patients with pha - ized amyloid formation [3, 13]. The variable region ryngeal amyloidosis suffer from discomfort in the of λ light chain restriction, with greater frequency pharynx – non-specific symptom for amyloidosis. in the literature, is known to be more amyloido - In the case of amyloidosis of Waldeyer’s ring pa- genic than κ. According to these data most of our tients suffer from an obstacle and discomfort in the patients (6/7) presented λ chain restriction. How - throat, likewise patient 2 with an amyloid tumour ever, in the Ma et al . [13] series, λ chain restriction sited in the right palatine tonsil [16]. In nasopha - accounted for 66% of cases. ryngeal localisation patients may present nasal Nevertheless, the importance of determining obstruction, epistaxis, postnasal discharge and whether amyloid deposits represent localized or sys - serous otitis media with effusion. In the presented temic amyloidosis is pointed out because of the dis - case only a slight ear problem and postnasal dis - tinctly shortened life expectancy in patients with charge were the symptoms. Therefore, almost in systemic forms of amyloidosis due to its involve - each case with laryngological symptoms, amyloi - ment in vital organs. Patients with systemic AL amy - dosis should also be taken into consideration. loidosis survive only up to 1 year if untreated [23]. In systemic amyloidosis the most frequent symp - According to the literature each localization, except tom in the head and neck region (in 15–20% of cas - the larynx, can be associated with haematological es) is enlargement of the tongue (macroglossia), malignancies and the plasma cell dyscrasias and which has a high association with plasma cell amyloidosis may co-exist in the head and neck [8, dyscrasias. It was also confirmed in 1 of our pa - 14]. Further diagnostic process to exclude systemic tients. The next symptoms in the sequence are amyloidosis is essential when a single focus of amy - cutaneous lesions around the upper eyelid, and loid deposits is verified. An invasive biopsy of the local changes in the trachea and larynx, where amy - gingival mucous membrane, abdominal subcuta -

Arch Med Sci 5 Wioletta Pietruszewska, Małgorzata Wągrowska-Danilewicz, Janusz Klatka neous fat, bone marrow or rectal biopsy is current - either colchicine monotherapy or with cyclophos - ly a very important part of the diagnostic procedure phamide (mostly AA form) in order to reduce amy - and the most affinitive and specific one, but dis - loid precursor protein production and to decrease crepancies in view of its necessity among authors deposition of amyloid in tissue [8, 15, 28]. Current - do exist [16, 23]. The absence of Congo red stain - ly, the hope for amyloidosis treatment is a small- ing of biopsy specimens from either of two sites molecule drug called CPHPC, which depletes the (primary tumour and predominantly rectum) indi - serum amyloid P (SAP) component, crucial in patho - cates that the amyloidosis is not systemic. Specif - genesis of amyloidosis. The new drug is a compet - ic organ involvement may also be excluded by radi - itive inhibitor of SAP and binds to amyloid fibrils ological and laboratory tests. It is necessary to and stabilizes them. Human trials for this molecule undergo a systemic workup which includes inter are under way [5, 9, 23]. Moreover, the results of alia laboratory tests of the urine in order to exclude molecular findings in patients with amyloidosis can Bence-Jones proteinuria, which is pathognomonic shed new light on the question why different for multiple myeloma, and radiological studies to lengths of amyloid fibrils can be responsible for dif - look for a primary tumour in order to exclude B-cell ferent organ and tissue deposition [29]. lymphoma [8, 18]. The diagnosis for systemic dis - Amyloidosis, although a rare disease, is not ease is also crucial in planning the proper treatment uncommon. Therefore, in each case of head and [24]. The extensive search for other locations of neck localized tumour, the need for a detailed and amyloid deposits was negative in all our patients comprehensive patient evaluation cannot be with localized amyloidosis; only patient 7 with overemphasized. Moreover, the role of a high index macroglossia was finally diagnosed as having sys - of amyloidosis suspicion in evaluating a patient temic AL amyloidosis. with a head and neck tumour or swelling should be Unlike systemic amyloidosis, however, localized taken into consideration. Also, there is a need for amyloidosis has an excellent prognosis. In contrast a long close follow-up in all the patients after local - to Alaani et al . [4] and Zhuang et al . [19], in the ized AL amyloidosis treatment due to recurrences. available literature only one case of progression from localized to systemic amyloidosis was proved. References Penner and Muller [8] revealed development of Hodgkin’s lymphoma after 12 years of the initial 1. von Rokitansky KF. Handbuch der pathologischen Ana- tomie. Braumuller&Seidel, Vienna 1842; 209-49. treatment of localized amyloidosis of the tongue. 2. Virchow R. Bav and Zussmmersetzying der Corporci Cases of local recurrences are described more often Amalacca des Menschen. Vehr Phys Med Geswurzlurg [6]. Ma et al . [13] and also Penner and Muller [8] 1851; 2: 51-3. reported patients with multiple recurrences of local - 3. Westermark P. Aspects on human amyloid forms and their ized amyloidosis, each treated with surgical exci - fibril polypeptides. FEBS J 2005; 272: 5942-9. sions, using carbon dioxide laser or conventional 4. Alaani A, Warfield AT, Pracy JP. Management of laryngeal surgery. In the present data no recurrences of the amyloidosis. J Laryngol Otol 2004; 118: 279-83. 5. Pepys MB, Herbert J, Hutchinson WL, et al. Targeted localised amyloidosis were observed in 4–12 years pharmacological depletion of serum amyloid P component of a follow-up. Although amyloidosis usually man - for treatment of human amyloidosis. Nature 2002; 417: ifests as a slow-growing, benign tumour, it may be 254-9. locally aggressive and produce osteolysis. Hegarty 6. Thompson LD, Derringer GA, Wenig BM. Amyloidosis of and Rao [25] and also Patel et al . [26] reported cas - the larynx: a clinicopathologic study of 11 cases. Mod es of the nasopharynx involving the skull base. In Pathol 2000; 13: 528-35. 7. Aisen PS, Gauthier S, Ferris SH, et al. Tramiprosate in mild- these cases computed tomography or magnetic res - to-moderate Alzheimer’s disease – a randomized, double- onance imaging is helpful in revealing any bony blind, placebo-controlled, multi-centre study (the Alphase destruction or intracranial extension [4, 6]. In com - Study). Arch Med Sci 2011; 7: 102-11. puted tomography amyloidosis appears as marked 8. Penner CR, Muller S. Head and neck amyloidosis: a clini - thickening of the soft tissue, whereas in magnetic copathologic study of 15 cases. Oral Oncol 2006; 42: resonance imaging amyloid deposits have the same 421-9. 9. Westermark P, Benson MD, Buxbaum JN, et al.; Nomen - signal as skeletal muscle, whilst neoplastic tumour clature Committee of the International Society of shows a significant degree of contrast enhance - Amyloidosis. Amyloid: toward terminology clarification. ment [27]. Report from the Nomenclature Committee of the The mainstay of localized amyloidosis treatment International Society of Amyloidosis. Amyloid 2005; 12: is conservative excision with either an open oper - 1-4. ation or carbon dioxide laser [4, 21]. Therapy includ - 10. Yoshida T, Matsuda M, Katoh N, et al. Long-term following corticosteroids and radiotherapy has been up of plasma cells in bone marrow and serum free light chains in primary systemic AL amyloidosis. Intern Med shown to be ineffective [22]. 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6 Arch Med Sci Amyloidosis of the head and neck: a clinicopathological study of cases with long-term follow-up

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