Departments of 1Pulmonary Medicine, 2Radiodiagnosis and 3Pathology & Laboratory Medicine, All India Institute of Medical Sciences, Bhopal, India *Corresponding Author’s e-mail: khuranaalkesh@gmail.com تكون احلصّيات الدقيقة يف حويصالت الرئة اهلوائية حالة نادرة غالباً ما ُيطَأ يف تشخيصها األكي�ض كورانا، راجي�ض ماليك، جيتندرا �شارما، اأوجوال كورانا، ديبتي جو�شي، ابي�شيك جويال abstract: Pulmonary alveolar microlithiasis (PAM) is an uncommon entity which can pose a diagnostic challenge. We report a 45-year-old female who was referred to the All India Institute of Medical Sciences, Bhopal, India, in 2017 with a two-year history of progressively worsening dyspnoea and dry coughing. She had been previously diagnosed with pulmonary tuberculosis elsewhere and prescribed antitubercular therapy; however, there was little improvement in her symptoms. Following referral, the patient was diagnosed with PAM based on high-resolution computed tomography findings and the abundance of lamellar microliths in a bronchoalveolar lavage sample. She was subsequently managed symptomatically and enrolled in a rehabilitation programme. Keywords: Calcinosis; Pulmonary Alveolar Microlithiasis; Pulmonary Tuberculosis; Misdiagnosis; Case Report; India. حتدًيا الغالب يف متثل والتي �شائعة الغري املر�شية احلالت من الهوائية الرئة حوي�شالت يف الدقيقة احل�شّيات تكون يعترب امللخ�ص: للعلوم الهند عموم معهد اإىل اأحيلت عاًما 45 العمر من بالغة امراأة عن عبارة هي والتي احلالت هذه اأحد ت�شجيل هنا يتم ت�شخي�شًيا، الطبية يف مدينة بوبال يف الهند يف عام 2017 وهي تعاين منذ �شنتني من تدهور تدريجي يف �شيق التنف�ض و�شعال جاف، مت ت�شخي�ض ن الأعرا�ض طفيفًا، بعد معاينة املراأة �شابقًا يف مكان اآخر مبر�ض ال�شل الرئوي وو�شف لها اآنذاك العالج امل�شاد لل�شل، ولكن كان حت�شُّ املري�شة، مت ت�شخي�شها بالإ�شابة باحل�شّيات الدقيقة يف حوي�شالت الرئة الهوائية بناءاً على ما اأظهرته نتائج الت�شوير املقطعي عايل الدقة والك�شف عن وجود ح�شّيات دقيقة بوفرة يف عينة اإفرازات الق�شبات الهوائية، متَّ عالج املراأة عن طريق تخفيف الأعرا�ض واإدخالها يف برنامج اإعادة تاأهيل. الكلمات املفتاحية: التكلُّ�ض؛ تكون احل�شّيات الدقيقة يف حوي�شالت الرئة الهوائية؛ ال�شل الرئوي؛ خطاأ الت�شخي�ض الطبي؛ تقرير حالة؛ الهند. Pulmonary Alveolar Microlithiasis A commonly misdiagnosed rare entity *Alkesh Khurana,1 Rajesh Malik,2 Jitendra Sharma,2 Ujjawal Khurana,3 Deepti Joshi,3 Abhishek Goyal1 Sultan Qaboos University Med J, May 2018, Vol. 18, Iss. 2, pp. e236–238, Epub. 9 Sep 18 Submitted 3 Jan 18 Revision Req. 30 Jan 18; Revision Recd. 5 Feb 18 Accepted 18 Feb 18 casE rEport doi: 10.18295/squmj.2018.18.02.021 Pulmonary alveolar microlithiasis (pam)is a rare pathological entity not commonly encountered in routine clinical practice.1 Affected patients are often initially misdiagnosed and may undergo unnecessary treatment, such as antitubercular therapy in tuberculosis-endemic countries.2 As such, clinicians, radiologists and pathologists should be made aware of this entity so as to ensure a correct diagnosis. Case Report A 45-year-old female was referred to the Outpatient Pulmonology Department of the All India Institute of Medical Sciences, Bhopal, India, in 2017 with prog- ressively worsening dyspnoea and dry coughing over the past two years. There was no history of fever, anorexia or weight loss. She had previously undergone chest radiography at other centres and been diagnosed with pulmonary tuberculosis, for which she was pres- cribed antitubercular therapy. However, as there was very little improvement in her symptoms, she was sub- sequently referred to the All India Institute of Medical Sciences. At referral, a chest X-ray of the patient showed a bilateral dense micronodular pattern with fine reticulation predominantly at the bases, with a ‘sandstorm’-like appearance [Figure 1]. Similar findings were noted in serial radiographs from the previous year. Her total leukocyte count was 9,000/mm3, with a differential cell count of 56% neutrophils, 39% lympho- cytes, 4% monocytes and 1% eosinophils. Her haemo- globin levels were 13.1 g/dL and there was no history of haemoptysis since the onset of the illness. Other investi- gations, namely serum electrolytes (i.e. sodium, potassium, calcium, phosphorus and magnesium), renal function and liver function tests, were all within normal limits. Pulse oximetry indicated an oxygen saturation of 94% in room air. Pulmonary function tests yielded a classical restrictive pattern with a normal forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio and reduced FEV1 and FVC measurements (percent predicted values of 101%, 49% and 49%, respectively). An electrocardiogram and two-dimen- sional echocardiograph were essentially normal, with Alkesh Khurana, Rajesh Malik, Jitendra Sharma,Ujjawal Khurana, Deepti Joshi and Abhishek Goyal Case Report | e237 mildly elevated pulmonary artery pressure and no evidence of valvular heart disease. A high-resolution computed tomography (CT) scan revealed extensive dense interlobular and intralobular septal thickening of the parenchymal window and dense microcalcif- ication with a predominantly subpleural and peri- bronchial distribution, suggestive of pulmonary alveolar microlithiasis [Figure 2]. The next day, the patient underwent flexible bron- choscopy. Bronchoalveolar lavage (BAL) smears showed microliths, alveolar macrophages, ciliated columnar epithelial cells and multinucleate macrophage giant cells [Figure 3]. According to a differential cell count, the BAL sample consisted predominantly of alveolar macro- phages (91%). The microliths were spherical lamellate refractile fragile bodies which were predominantly extracellular and varied from 100–120 µm in size. There were between 2–12 nuclei in the multinucleate giant cells. A transbronchial lung biopsy (TBLB) showed sheets of foamy macrophages containing periodic acid-Schiff (PAS)-positive material in the subepithelium; however, no microliths were visible. The patient was subsequently diagnosed with PAM. Since a lung transplant was not feasible, she was managed symptomatically and enrolled in a rehabilitation programme. Her family was also screened for the disease using chest X-rays; however, no other cases were identified. Discussion PAM is a rare disease characterised by the widespread accumulation of minute calculi known as microliths in the lung parenchyma.1 The most likely aetiopatho- genesis of the disease is a mutation in the solute carrier family 34 member 2 (SLC34A2) gene, which leads to the ineffective uptake of phosphate from the alveoli and, therefore, the accumulation of calcium phosphate crystals.3 In the most comprehensive review of this entity to date, Castellana et al. analysed 1,022 PAM cases reported worldwide and noted that the disease had a slight male preponderance and most patients were in their second or third decade of life.1 A total of 80 patients were of Indian origin. A positive family history was reported in 37% of cases.1 In the current case, the patient was an Indian female in her fifth decade of life and had no family history of PAM or a similar illness. A diagnosis of PAM usually depends on the identification of various radiological and histopatho- logical features. In particular, the radiographical appear- ance of the patient’s lungs corresponds to the increasing severity of the disease.4 During the first stage, the radio- Figure 1: Chest X-ray of a 45-year-old female showing a bilateral dense micronodular pattern with fine reticulation. Figure 2: Computed tomography of the (A) lung window of a 45-year-old female showing diffuse dense interlobular and intralobular septal thickening with patchy ground glass opacities and (B) the mediastinal window showing diffuse microcalcification in both lungs with a subpleural and peribronchial distribution. Pleural and pericardial calcification (arrows) is also present. Figure 3: A: Wright Giemsa stain at x400 magnification showing spherical concentrically lamellate refractile micro- liths*. B: Papanicolaou stain of a bronchoalveolar lavage sample at x400 magnification showing a microlith (arrowhead), alveolar macrophage (black arrow) and ciliated columnar epithelial cell (white arrow). *The fine focusing of these bodies makes the background cells appear out of focus. Pulmonary Alveolar Microlithiasis A commonly misdiagnosed rare entity e238 | SQU Medical Journal, May 2018, Volume 18, Issue 2 Conclusion Despite its rarity, there is a need to increase the index of suspicion of PAM among clinicians, radiologists and pathologists in order to avoid misdiagnosis and unnecessary treatment. This case emphasises the combined role of high-resolution CT and BAL analysis in the diagnosis, thus avoiding the need for invasive procedures such as an open lung biopsy. References 1. Castellana G, Castellana G, Gentile M, Castellana R, Resta O. Pulmonary alveolar microlithiasis: Review of the 1022 cases reported worldwide. Eur Respir Rev 2015; 24:607−20. doi: 10.11 83/16000617.0036-2015. 2. Govindaraj V, Manju R, Jaganathan V, Udupa A, Hariprasad V, Saka V. Pulmonary alveolar microlithiasis: A case report. Int J Sci Study 2015; 3:212−15. doi: 10.17354/ijss/2015/190. 3. Corut A, Senyigit A, Ugur SA, Altin S, Ozcelik U, Calisir H, et al. Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet 2006; 79:650−6. doi: 10.1086/508263. 4. Castellana G, Castellana R, Fanelli C, Lamorgese V, Florio C. [Pulmonary alveolar microlithiasis: Clinical and radiological course of three cases according to conventional radiology and HRCT - A hypothesis for radiological classification]. Radiol Med 2003; 106:160−8. 5. Martínez-Girón R, Martínez-Torre S, Tamargo-Peláez ML, López-Cabanilles MD, Torre-Bayón C. Calcareous concretions and psammoma bodies in sputum smears: Do these similar structures have different clinical significance? Diagn Cytopathol 2014; 42:759−65. doi: 10.1002/dc.23120. 6. Jönsson ÅL, Simonsen U, Hilberg O, Bendstrup E. Pulmonary alveolar microlithiasis: Two case reports and review of the literature. Eur Respir Rev 2012; 21:249−56. doi: 10.1183/09059 180.00009411. 7. Monabati A, Ghayumi MA, Kumar PV. Familial pulmonary alveolar microlithiasis diagnosed by bronchoalveolar lavage: A case report. Acta Cytol 2007; 51:80−2. doi: 10.1159/000325688. 8. Casoni GL, Cordeiro CR Jr, Tomassetti S, Romagnoli M, Chilosi M, Cancellieri A, et al. The role of transbronchial biopsy in the diagnosis of diffuse parenchymal lung diseases: Pro. Rev Port Pneumol 2012; 18:57−60. doi: 10.1016/j.rppneu.2011.05.003. 9. Mariotta S, Ricci A, Papale M, De Clementi F, Sposato B, Guidi L, et al. Pulmonary alveolar microlithiasis: Report on 576 cases published in the literature. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21:173−81. 10. Prakash UB, Barham SS, Rosenow EC 3rd, Brown ML, Payne WS. Pulmonary alveolar microlithiasis: A review including ultrastruct- ural and pulmonary function studies. Mayo Clin Proc 1983; 58:290−300. 11. Kashyap S, Mohapatra PR. Pulmonary alveolar microlithiasis. Lung India 2013; 30:143−7. doi: 10.4103/0970-2113.110424. 12. Kanat F, Teke T, Imecik O. Pulmonary alveolar microlithiasis with epididymal and periurethral calcifications causing obstruc- tive azospermia. Int J Tuberc Lung Dis 2004; 8:1275. 13. Jackson KB, Modry DL, Halenar J, L’abbe J, Winton TL, Lien DC. Single lung transplantation for pulmonary alveolar microlith- iasis. J Heart Lung Transplant 2001; 20:226. doi: 10.1016/S1053- 2498(00)00500-3. logical findings are precalcific, although this is ident- ified very rarely. In the second stage, the lungs have a typical ‘sandy’ appearance, with scattered microliths and a delineated cardiac border.4 The density of the microliths then increases to obscure the cardiac borders in the third phase, before involving the pleura in the fourth phase, as noted in the current case.4 Despite these typical radiological features, it is not uncommon for patients to be misdiagnosed with tuberculosis, as in the present case, particularly in endemic areas.2 Despite this, the coexistence of tuberculosis and PAM is rare.1 Other diseases associated with a miliary dissem- ination include sarcoidosis, pneumoconiosis, haemo- siderosis, amyloidosis and mycosis. However, while the radiological appearance of calcifications are more intense in PAM cases, the symptoms of these other differential diagnoses are usually more severe.1 In order to confirm the diagnosis, a lung biopsy is required to demonstrate the presence of characteristic PAS-positive concentric calcareous lamellae around a central nucleus.1 The microliths should be differen- tiated from psammoma bodies, indicative of a malignant condition; these are similar in structure but occur as part of the epithelial cell group or as small tissue fragments.5 While the analysis of BAL samples is often inconclusive, the cytological findings in the current case were very characteristic of PAM, demonstrating both microliths and multinucleate giant cells.6,7 However, the presence of microliths in the BAL fluid rather than in the TBLB specimen was unusual, particularly as the latter technique is usually more sensitive for diffuse lung disease.8 This may have been because of the blind nature of the technique. In general, less than 50% of PAM cases have positive TBLB findings.9 However, pulmonary function tests may have a support- ive role by revealing a restrictive pattern, as seen in the present case.10 Once diagnosed, the course of the illness is variable and can either remain stable or become progressively worse, resulting in cor pulmonale.11 However, since the onset is insidious and the clinical course is generally quite slow, it can be difficult to definitively establish the onset of the disease. Furthermore, since the SLC- 34A2 gene is expressed in certain extrapulmonary tissues—including the testicles, kidneys, pancreas, intestines, breasts, ovaries, liver and prostate—some patients may also have extrapulmonary symptoms, such as infertility, azoospermia, haematuria and gall- stones.11,12 Currently, no medical or genetic therapy is yet available, with chelating agents and therapeutic lung lavage reported to be ineffective.10 To date, lung transplantation is the only accepted treatment, with survival up to 15 years reported without recurrence.13 https://doi.org/10.1183/16000617.0036-2015 https://doi.org/10.1183/16000617.0036-2015 https://doi.org/10.17354/ijss/2015/190 https://doi.org/10.1086/508263 https://doi.org/10.1002/dc.23120 https://doi.org/10.1183/09059180.00009411 https://doi.org/10.1183/09059180.00009411 https://doi.org/10.1159/000325688 https://doi.org/10.1016/j.rppneu.2011.05.003 https://doi.org/10.4103/0970-2113.110424 https://doi.org/10.1016/S1053-2498%2800%2900500-3 https://doi.org/10.1016/S1053-2498%2800%2900500-3