Dermatology: Practical and Conceptual Research | Dermatol Pract Concept 2019;9(2):7 119 Dermatology Practical & Conceptual Mucous Membrane Pemphigoid-Associated Malignancies: Case Series and a Brief Overview of the Literature Michelangelo La Placa1, Riccardo Balestri1, Federico Tartari1, Andrea Sechi1, Francesca Ferrara1, Camilla Loi1, Annalisa Patrizi1, Federico Bardazzi1 1 Dermatology Division, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy Key words: mucous membrane pemphigoid, malignancy, autoimmune bullous disorders, paraneoplastic pemphigus, laminin-332, blistering diseases, laminin-5, anti-epiligrin, cicatricial pemphigoid, adenocarcinoma Citation: La Placa M, Balestri R, Tartari F, Sechi A, Ferrara F, Loi C, Patrizi A, Bardazzi F. Mucous membrane pemphigoid-associated malignancies: Case series and a brief overview of the literature. Dermatol Pract Concept. 2019;9(2):119-125. DOI: https://doi.org/10.5826/ dpc.0902a07 Accepted: February 6, 2019; Published: April 30, 2019 Copyright: ©2019 La Placa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: None. Competing interests: The authors have no conflicts of interest to disclose. Authorship: All authors have contributed significantly to this publication. Corresponding author: Michelangelo La Placa, MD, Dermatology Division, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Massarenti 1, 40138, Bologna, Italy. Email: michelangelo.laplaca@unibo.it Background: Mucous membrane pemphigoid (MMP) is a heterogeneous group of blistering disorders affecting the mucosae with or without skin involvement, characterized by the presence of autoantibod- ies to components of the basement membrane zone, including the bullous pemphigoid antigen BP180 and β4 integrin. Current literature has shown that a minority of patients present circulating antibodies to laminin-332 and this population seems to be associated with a relatively high risk of malignancy. Objective: To present our personal case series of patients with MMP-associated malignancy from a dermatology university hospital. Methods: Twenty-two patients affected by MMP were seen in the period between 2001 and 2016; in 4 patients (18%) an associated cancer was detected. Results: These patients were 2 men and 2 women, with a mean age of 69.7 years (range, 48-83). The associated malignancies included a breast cancer, a pancreatic adenocarcinoma, a metastatic laryngeal carcinoma, and a hepatic carcinoma. All patients had negative results for both BP180 and laminin-332 autoantibodies. Conclusion: We confirm that MMP patients have a relatively high possibility of developing a solid cancer, but the autoantibody detection is not mandatory and is probably correlated with the severity of the disease. ABSTRACT Introduction Mucous membrane pemphigoid (MMP), formerly cicatricial pemphigoid, is a rare heterogeneous group of autoimmune subepithelial blistering disorders involving the mucous mem- branes and occasionally the skin with a chronic course and tendency toward scarring [1]. Previously, other names have been used to describe these conditions, including benign MMP, anti-laminin-5 cicatricial pemphigoid, oral pemphi- goid, and ocular pemphigoid. Because it is difficult to clini- 120 Research | Dermatol Pract Concept 2019;9(2):7 Ta b le 1 . C li n ic al a n d S er o lo gi ca l D at a Fr o m M M P P at ie n ts W it h A ss o ci at ed M al ig n an ci es a t th e U n iv er si ty o f B o lo gn a N o . S e x /A g e a t D ia g n o si s o f M M P ( y r) S it e s In v o lv e d In te rv a l B e tw e e n M M P O n se t a n d Tu m o r D ia g n o si s A ss o ci a te d M a li g n a n cy B P A n ti g e n s B P 1 8 0 a n d B P 2 3 0 A n ti - la m in in -3 3 2 Tr e a tm e n t a n d F o ll o w -u p 1 F /6 6 ( 2 0 1 4 ) O ra l/ ge n it al , o cu la r 1 y r b ef o re M M P o n se t B re as t ca n ce r N eg at iv e N eg at iv e M M P d ev el o p ed a ft er 1 y r o f su rg er y fo r b re as t ca n ce r. F o ll o w -u p t re at m en t w it h d ap so n e 2 0 0 m g/ d a n d p re d n is o n e 7 .5 m g/ d w it h o u t re cu rr en ce . 2 M /8 2 ( 2 0 1 4 ) Sk in /o ra l/ o cu la r 1 y r af te r M M P o n se t M et as ta ti c la ry n ge al SC C N eg at iv e N eg at iv e D u ri n g m et h yl p re d n is o lo n e tr ea tm en t, t h e p at ie n t d ev el o p ed l ar yn ge al S C C th at b ec am e m et as ta ti c af te r 1 y r. T h e st er o id w as d is co n ti n u ed a n d t re at m en t w it h d ap so n e 2 0 0 m g/ d i n a d d it io n t o r ad io th er ap y an d c h em o th er ap y w as st ar te d . H e d ie d a ft er 6 m o s. 3 M /4 8 ( 2 0 1 3 ) O ra l 3 y rs a ft er M M P o n se t P ro st at ic A C N eg at iv e N D O ra l M M P, i n vo lv in g ex cl u si ve ly t h e h ar d p al at e an d t h e gu m s. S ys te m ic st er o id s an d d ap so n e w it h f av o ra b le r es u lt s u n ti l co m p le te r em is si o n . P ro st at ic A C a ft er 3 y rs . F o ll o w -u p w it h o u t M M P r el ap se s. 4 F /8 3 ( 2 0 1 6 ) O cu la r 1 y r af te r M M P o n se t H ep at ic ca n ce r N eg at iv e N eg at iv e B re as t ca n ce r at a ge 7 2 , m as te ct o m y, a n d l iv er c ir rh o si s fo r ch ro n ic h ep at it is , w it h e ye M M P, u n d er t re at m en t w it h m et h yl p re d n is o lo n e. H ep at o ca rc in o m a d ev el o p ed r ec en tl y d u ri n g fo ll o w -u p . A C = a de no ca rc in om a; B P = bu llo us p em ph ig oi d; N D = n ot d on e; S C C = s qu am ou s ce ll ca rc in om a. cally distinguish the various MMP subgroups, the collective term MMP is now accepted [2]. MMP commonly affects the oral mucosa, but ocular and nasal epithelia, the first aerodigestive tract and the genitals may be involved. Cutaneous involvement may be absent or limited. MMP usually affects patients aged between 60 and 80 years, with a female prevalence [1-3]. The disease is mainly controlled with corticosteroids and other immunosuppressive drugs, including cyclosporine, mycophenolate, cyclophospha- mide, and azathioprine [3]. Most of the MMP autoantibody profile shares the same target antigens of other autoimmune blistering diseases from the pemphigoid group and paraneoplastic pemphigus, namely circulating IgG and/or IgA autoantibodies targeting the basement membrane zone (BMZ) components, includ- ing the bullous pemphigoid antigens BP180 and BP230, and the β4 integrin [1-6]. Current evidence demonstrates that a minority of MMP patients with autoantibodies to IgG anti- laminin-332 (formerly anti-laminin-5 or anti-epiligrin) have an increased relative risk of cancer [1,7]. Previously, this subgroup was named anti-epiligrin cicatricial pemphigoid (AECP), to differentiate it from the majority of cicatricial pemphigoid patients without these specific autoantibodies. Finally, there is no report of MMP-associated malignancies with autoantibodies to BP180 [1,2,8-14]. We present a case series of MMP patients with associated malignancies and a brief overview of the current literature. Case Series During the period between 2001 and 2016, at the Department of Dermatology at the University of Bologna, we diagnosed and followed up 22 patients affected by MMP. From this group, we selected 4 individuals (18%) who developed a solid tumor (a breast cancer, a pancreatic adenocarcinoma, a metastatic laryngeal carcinoma, and a hepatocarcinoma) before the MMP diagnosis or during the MMP follow-up. They were 2 men and 2 women, with a mean age of 69.7 years (range, 48-83). In general, our patients had mainly oral and/or genital mucous involvement. Only patient 2 had con- comitant skin lesions, characterized by blisters and erosions on the trunk and limbs, and patient 4 had exclusive conjunc- tival involvement, undergoing a complete loss of eyelashes due to synechiae. Cancer detection was preceding in case 1 (diagnosed 1 year before MMP) and metachronous in the remaining cases: 1 year after MMP in cases 2 and 4, and 3 years after in case 3. All patients’ data, treatment, and follow- up are summarized in Table 1. Another patient, a 73-year-old woman, received the diagnosis of breast cancer 6 years pre- ceding MMP occurrence. She is still under follow-up in our Research | Dermatol Pract Concept 2019;9(2):7 121 lular matrix [1,2,6-9]. These individuals cannot be distin- guished clinically from those with other variants of MMP [10]. Because it has been reported that these patients with anti-laminin-332 have an increased relative risk of develop- ing cancer, in particular adenocarcinoma, prompt diagnosis and treatments are crucial [8-12]. Various pathogenetic hypotheses have been put forward, including the theory that tumor cells secrete laminin-332 with the consequent loss of keratinocyte adhesion and blister formation [10]. A literature search revealed several case reports and ret- rospective cohort studies regarding MMP and malignancy [8,12-36]. In particular, Egan et al described a cohort of 35 patients affected by AECP followed up in a period of 12 years; 10 patients (28.6%) developed a solitary cancer [8]. Eight of these patients had cancer after the onset of AECP, most within 12 to 14 months, and all deaths were cancer-related. The associated malignancies included 3 lung, 3 stomach, 2 colon, and 2 endometrial cancers. They estimated a relative risk of 6.8% for solid cancer, but 15.4% if diagnosed within the first year of blister formation. They also documented the short interval occurring between the onset of AECP and cancer (average 14 months). This was the first cohort study regarding MMP and associated malignancies. Later, Letko et al have published a retrospective study of 79 patients affected by MMP [11]. Only in 3 patients was a cancer associated with MMP; a breast ductal carcinoma in situ, a lung squamous cell carcinoma, and a colon adenocarcinoma. Three other oncology patients had been excluded from the study because the cancer diagnosis preceded the MMP (13, clinic, but was excluded from the study because of the long interval between cancer occurrence and the MMP diagnosis. An MMP diagnosis was made by combining the clinical and histopathological findings. In particular, clinical findings included active mucous membrane involvement characterized by blisters and/or erosions. In addition, direct and indirect immunofluorescence from perilesional mucosa revealed a lin- ear deposition of IgG and/or C3 at the BMZ and circulating IgG anti-BMZ autoantibodies, respectively (Figure 1). Immu- noblot analysis was negative for anti-BP180 and anti-BP230 autoantibodies, as well as anti-purified human laminin-332. The investigation described was carried out on residual biopsy sections following diagnostic analysis during the course of institutional diagnostic services, and the study was exempted from institutional review board review. Discussion MMP is an autoimmune bullous disorder with predominant or exclusive mucosal involvement. As reported for para- neoplastic pemphigus and bullous pemphigoid, MMP is a pathogenetic example of cell-mediated immunity involve- ment, characterized by the presence of different autoantibody responses to basement membrane antigens, including the BP180 and BP230, or β4 integrin [3]. Moreover, whereas most of MMP patients share BP180 autoantigen and oral or cutaneous involvement [12], a minority of individuals express laminin-332 antigen, which is a glycoprotein that interacts with other BMZ molecules to stabilize the extracel- A D B E C F Figure 1. (A) Ocular MMP with conjunctival involvement, with symblepharon formation. (B) Polymorphic manifestation of MMP with cu- taneous involvement, characterized by tense, serous, or hemorrhagic bullae. (C) Oral MMP with hemorrhagic crusting and lip erosions. (D) Low magnification of subepidermal blister with inflammatory cell infiltrate (hematoxylin and eosin [H&E], ×4). (E,F) MMP inflammatory infiltrate of the upper dermis, with numerous eosinophils (H&E, ×10; H&E, ×20). [Copyright: ©2019 La Placa et al.] 122 Research | Dermatol Pract Concept 2019;9(2):7 T ab le 2 c o n ti n u es n ex t p ag e S tu d y S tu d y D e si g n M M P A n ti b o d ie s D ia g n o si s o f M a li g n a n cy T im e o f M a li g n a n cy D ia g n o si s Tr e a tm e n t a n d F o ll o w -u p T an iu ch i et a l, 1 9 9 9 [ 1 5 ] A E C P c as e re p o rt L am in in -5 G as tr ic A C S M in o cy cl in e 2 0 0 m g/ d a n d n ic o ti n am id e 1 ,5 0 0 m g/ d w it h o u t im p ro ve m en t. B u ll o u s le si o n s d is ap p ea re d a ft er g as tr ec to m y, b u t m et as ta se s o cc u rr ed a ft er 8 m o s. C h am b er la in e t al , 2 0 0 4 [ 1 6 ] C as e re p o rt ( 2 ca se s) L am in in -5 b y in d ir ec t im m u n o fl u o re sc en ce U te ri n e C A a n d o va ri an C A ( b o th m et as ta ti c) M ( b o th ca se s) In b o th p at ie n ts , r em is si o n o f b u ll o u s d is ea se w as o b ta in ed a ft er h ys te re ct o m y. Y am ad a et a l, 2 0 1 2 [1 7 ] C as e re p o rt L am in in -3 3 2 T h yr o id C A , k id n ey C A a n d r et ro p er it o n ea l sa rc o m a S Sk in a n d m u co sa l le si o n s h ea le d a ft er s u rg er y an d t re at m en t w it h p u ls e st er o id t h er ap y an d p la sm ap h er es is . F u k u sh im a et a l, 2 0 0 8 [ 1 8 ] A E C P c as e re p o rt N A P ro st at ic C A M Sk in l es io n s w er e re si st an t to t h er ap y (o ra l p re d n is o lo n e 3 0 m g, m in o cy cl in e h yd ro ch lo ri d e 1 0 0 m g, a n d n ic o ti n am id e 1 ,5 0 0 m g) , b u t im p ro ve d a ft er ad m in is tr at io n o f d ap so n e 1 0 0 m g/ d . M at su sh im a et a l, 2 0 0 4 [ 1 9 ] A E C P c as e re p o rt L am in in -5 b y im m u n o b lo t L u n g ca rc in o m a M M M P i m p ro ve d a ft er p re d n is o n e an d m in o cy cl in e, b u t th e p at ie n t d ie d a ft er tr ac h eo st o m y. Se tt er fi el d e t al , 1 9 9 9 [ 2 0 ] C as e re p o rt L am in in -5 N o n -s m al l- ce ll l u n g C A P P re d n is o lo n e 4 0 m g/ d a n d a za th io p ri n e 5 0 m g/ d a n d t h er ea ft er d ap so n e 1 0 0 m g/ d a n d c yc lo sp o ri n e 3 m g/ k g/ d d id n o t im p ro ve u n ti l th e ti m e o f d ea th . Sh ib u ya e t al , 2 0 1 2 [2 1 ] C as e re p o rt L am in in -3 3 2 γ 2 su b u n it b y im m u n o b lo t O va ri an C A S P re d n is o lo n e 3 0 m g/ d w as p ar ti al ly e ff ec ti ve . M it su ya e t al , 2 0 0 8 [2 2 ] C as e re p o rt L am in in -5 γ 2 s u b u n it M et as ta ti c o va ri an C A M P re d n is o lo n e 4 0 m g/ d a n d m in o cy cl in e 2 0 0 m g/ d , t h en i n tr av en o u s im m u n o gl o b u li n s w it h o u t im p ro ve m en t. Sa ra va n an e t al , 2 0 0 6 [ 2 3 ] C as e re p o rt N A R en al C A P T re at m en t w it h d ap so n e, p re d n is o lo n e, a n d a za th io p ri n e, b u t d is ea se p ro gr es se d . Y o u n g et a l, 2 0 1 1 [2 4 ] C as e re p o rt L am in in -3 3 2 M et as ta ti c p ro st at e C A M O rc h ie ct o m y an d h o rm o n e d ep ri va ti o n t h er ap y. M yc o p h en o la te m o fe ti l 1 ,5 0 0 m g an d p re d n is o n e cu re d t h e b li st er s. O st le re e t al , 1 9 9 2 [2 5 ] C as e re p o rt N D M et as ta ti c p an cr ea s C A P N o r es p o n se w it h p re d n is o lo n e an d d ap so n e, a n d t h en p re d n is o lo n e an d cy cl o p h o sp h am id e. U ch iy am a et a l, 2 0 0 0 [ 2 6 ] A E C P c as e re p o rt L am in in -5 s er u m im m u n o p re ci p it at io n G as tr ic C A P M M P r es o lv ed a ft er g as tr ec to m y. D ai n ic h i et a l, 2 0 1 1 [ 2 7 ] C as e re p o rt L am in in -3 3 2 H ep at o ce ll u la r C A i n ci rr h o si s M M M P n o t re sp o n si ve t o m in o cy cl in e 2 0 0 m g/ d , d ap so n e 7 5 m g/ d , a n d o ra l p re d n is o lo n e 3 0 m g/ d . P at ie n t d ie d . P o ll ia ck , 1 9 6 8 [ 2 8 ] C as e re p o rt N D T h yr o id A C P M M P n o t re sp o n si ve t o p re d n is o lo n e an d s u lf ap yr id in e u n ti l fa ta l o u tc o m e. Ta b le 2 . C as e R ep o rt s o f M M P -A ss o ci at ed M al ig n an ci es F ro m t h e L it er at u re Research | Dermatol Pract Concept 2019;9(2):7 123 S tu d y S tu d y D e si g n M M P A n ti b o d ie s D ia g n o si s o f M a li g n a n cy T im e o f M a li g n a n cy D ia g n o si s Tr e a tm e n t a n d F o ll o w -u p H o p e- R o ss e t al , 1 9 9 0 [ 2 9 ] C as e re p o rt N D E so p h ag ea l C A P E x cl u si ve o cu la r in vo lv em en t tr ea te d w it h t o p ic al d ex am et h as o n e, a ce ty l cy st ei n e, a n d c yc lo sp o ri n e w it h g o o d c li n ic al r es p o n se . G re er e t al , 1 9 8 0 [3 0 ] C as e re p o rt N D M et as ta ti c lu n g C A P A ft er r ad io th er ap y, M M P w as w el l co n tr o ll ed w it h p re d n is o n e. K il b y, 1 9 6 5 [ 3 1 ] C as e re p o rt N D M et as ta ti c p an cr ea s C A P U n su cc es sf u l tr ea tm en t w it h 2 0 m g/ d o f p re d n is o lo n e. G ib so n e t al , 1 9 9 7 [3 2 ] A E C P c as e re p o rt L am in in -5 b y im m u n o p re ci p it at io n L u n g C A P G o o d r es p o n se o f M M P w it h m u lt ip le c o u rs es o f p re d n is o n e, cy cl o p h o sp h am id e, a n d d ap so n e. F u ji m o to e t al , 1 9 9 8 [ 3 3 ] A E C P c as e re p o rt N D G as tr ic C A S A ft er g as tr ec to m y, s p le n ec to m y, a n d c h o le cy st ec to m y, M M P h ea le d a n d co rt ic o st er o id s w er e d is co n ti n u ed . F ew w ee k s af te r b et am et h as o n e w as st o p p ed , b li st er s re la p se d a n d t h e p at ie n t d ie d o f m et as ta se s. D in g et a l, 2 0 1 4 [3 4 ] A E C P c as e re p o rt N eg at iv e C er vi ca l A C P M M P h ea le d a ft er h ys te ro an n es si ec to m y an d l ym p h ad en ec to m y. F u k u ch i et a l, 2 0 1 3 [3 5 ] C as e re p o rt L am in in -3 3 2 a n d B P 2 3 0 p o si ti ve U n k n o w n o ri gi n A C P M M P r em is si o n w it h p re d n is o n e 6 0 m g/ d , b u t th e p at ie n t d ie d a n d d ia gn o si s o f lo w -g ra d e A C o f u n k n o w n p ri m ar y si te w as m ad e af te r au to p sy . D em it su e t al , 2 0 0 9 [3 6 ] C as e re p o rt L am in in -3 3 2 a n d B P 1 8 0 P an cr ea s C A S B et am et h as o n e 4 m g an d p la sm a ex ch an ge g av e b en efi t to M M P r es o lu ti o n , b u t p at ie n t d ie d o f in tr ah ep at ic c h o la n gi ti s fo ll o w ed b y se p si s. Sh an n o n e t al , 2 0 0 3 [ 1 4 ] C as e re p o rt L am in in -5 b y im m u n o b lo t L ar ge B -c el l n o n - H o d gk in l ym p h o m a M M M P d ev el o p ed a ft er 2 c yc le s o f ch em o th er ap y w it h r em is si o n o f ly m p h o m a. H ig h -d o se s ys te m ic s te ro id s an d a za th io p ri n e co n tr o ll ed t h e p em p h ig o id u p t o r es o lu ti o n . Sa d le r et a l, 2 0 0 7 [9 ] A E C P c as e re p o rt a n d re p o rt ed c as es re vi ew L am in in -5 b y im m u n o b lo t M yc o si s fu n go id es M C u ta n eo u s ly m p h o m a co n tr o ll ed w it h t o p ic al c lo b et as o l fo r 1 2 y ea rs b ef o re o cc u rr en ce o f o ra l an d n as al M M P. A C = a de no ca rc in om a; B P = bu llo us p em ph ig oi d; C A = c ar ci no m a; M = m et ac hr on ou s; N A = n ot a va ila bl e; N D = n ot d et ec te d; P = p re ce di ng th e ca nc er d ia gn os is ; S = s yn ch ro no us . Ta b le 2 . (C o n ti n u ed ) 124 Research | Dermatol Pract Concept 2019;9(2):7 5, and 4 years, respectively). In another report, Sadler et al described a patient with mycosis fungoides treated for 12 years with topical clobetasol ointment who developed oral and nasal erosions; histopathology led to the diagnosis of AECP [9]. This is the first association between MMP and lymphoma. Moreover, the authors provided a summary overview of all MMP (or AECP) cancer-associated cases published until 2007, including a letter from Shannon and colleagues [14], reporting a case of cicatricial pemphigoid and non-Hodgkin lymphoma. More recently, Bernard and colleagues analyzed a large cohort of 154 MMP patients, and an associated neoplasia was found in 18 (11.7%) of them [13]. In this French study, the prevalence and significance of anti-laminin-332 was analyzed, showing that the presence of these antibodies is directly correlated with the severity of the disease, but not exclusively with the presence of a neoplasm. In fact, of these 18 patients, they showed that only 2 (6.4%) were laminin-332 positive, while 16 (13%) were laminin-332 negative, concluding that this frequency does not differ from that of the general population in the same age range. It is noteworthy, finally, that in most of these cases the interval between cancer detection and MMP occurrence was very long (more than 8 years), and the cancer diagnosis frequently preceded the MMP occurrence. On the other hand, case reports published to date include 23 MMP or AECP patients with 25 solid tumors, in particular lung, gastric, ovarian, cervical, and pancreatic adenocarcino- mas; and renal, prostatic, thyroid, hepatocellular, and esopha- geal carcinomas [8,14-36]. In addition, a case of large B-cell non-Hodgkin lymphoma and a case of mycosis fungoides are cited above [8,14]. Although it is sometimes impossible to clarify the time of cancer detection, in 16 cases the diagnosis of MMP preceded the tumor diagnosis or was synchronous (11 and 5 cases, respectively), whereas in 9 patients the bul- lous disorder occurred after the cancer detection (metachro- nous) (Table 2). Determining a true paraneoplastic syndrome is often impossible. In fact, most neoplasms are initially occult and asymptomatic. In particular, a true paraneoplastic syndrome comprises the contemporaneous presence (or detection) of both dermatosis and cancer, with resolution of symptoms after cancer healing, and possible recurrence after cancer relapse. Therefore, the term “paraneoplastic” is used only for a subtype of pemphigus, while the term “associated malignan- cies” must be preferred in the other autoimmune blistering disorders, including MMP [37]. In our case series, 3 patients developed the malignancy 1 to 3 years after the MMP diagnosis. A woman had breast cancer 1 year before MMP occurrence. Although 1 of our patients died from metastases 1.5 year after MMP diagnosis (case 2), the others cleared their bullous disease after cancer removal and are still under follow-up (range, 2-5 years) in our clinic without recurrences. Conclusions The clinical importance of determining specific antibodies in autoimmune blistering disorders is well known. For example, the presence of BP180 and/or BP230 in bullous pemphigoid may represent an active disease also in the absence of clinical symptoms [38]. In this regard, various studies demonstrate the correlation between laminin-332 MMP and cancer, under- scoring the importance of immunological diagnosis of these autoantibodies [7,10]. On the other hand, and in accordance with the recent study by Bernard and coworkers [13], our data demonstrate the relatively frequent association of MMP with a solid cancer, but no significant correlation with autoantibody detection. 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