When lung and blood meet| Rassegna di Patologia dell'Apparato Respiratorio

Abstract

• 68 years-old male, former smoker (26 P/Y), former truck driver.
• Premature hair graying. No history of any alcohol abuse. No environmental exposure
• Familial clinical history: not relevant.
• Past medical history: not relevant.
• Recent medical history: properly treated Helicobacter Pylori associated chronic gastritis; macrocytic anemia and thrombocytopenia.

In July 2023 he started complaining for asthenia, arthralgia, dyspnea on effort and dry cough.

A CT scan of the thorax documented a coarse nodularity associated with perilobular pattern in the dorsal segment of the right upper lobe, and multiple sub pleural rounded consolidations without air bronchograms, sometimes associated with “halo sign”, in both lower lobes (Fig. 1).

He started a course with steroids and a CT scan performed in October 2023 documented the reduction in number and volume of the lung infiltrates.

In December 2023 the patient presented with respiratory failure needing non-invasive ventilation due to interstitial pneumonia caused by SARS-CoV-2 infection.

He was referred to us with a diagnosis of post-COVID pulmonary fibrosis.

At admission he still claimed for asthenia, arthralgia, dyspnea on effort and dry cough and reported also an episode of hemoptysis in recent past. Fine inspiratory bibasilar crackles were found at the physical examination of the chest. Neurological examination was not relevant. Laboratory tests documented macrocytic anemia, mild thrombocytopenia and mild increase of inflammatory markers. Serum levels of cobalamin, folic acid, glucose and homocysteine were normal. Autoantibodies panel, including those related to inflammatoy myosites/anti-synthetase syndrome and ANCA were negative. Pulmonary function tests revealed mild restrictive pattern and moderate reduction in DLCO. Six minute walking test documented desaturation on effort.

Articolo

1. 68 years-old male, former smoker (26 P/Y), former truck driver.
2. Premature hair graying. No history of any alcohol abuse. No environmental exposure
3. Familial clinical history: not relevant.
4. Past medical history: not relevant.
5. Recent medical history: properly treated Helicobacter Pylori associated chronic gastritis; macrocytic anemia and thrombocytopenia.

Clinical and radiologic background

In July 2023 he started complaining for asthenia, arthralgia, dyspnea on effort and dry cough.

A CT scan of the thorax documented a coarse nodularity associated with perilobular pattern in the dorsal segment of the right upper lobe, and multiple sub pleural rounded consolidations without air bronchograms, sometimes associated with “halo sign”, in both lower lobes (Fig. 1).

He started a course with steroids and a CT scan performed in October 2023 documented the reduction in number and volume of the lung infiltrates.

In December 2023 the patient presented with respiratory failure needing non-invasive ventilation due to interstitial pneumonia caused by SARS-CoV-2 infection.

He was referred to us with a diagnosis of post-COVID pulmonary fibrosis.

At admission he still claimed for asthenia, arthralgia, dyspnea on effort and dry cough and reported also an episode of hemoptysis in recent past. Fine inspiratory bibasilar crackles were found at the physical examination of the chest. Neurological examination was not relevant. Laboratory tests documented macrocytic anemia, mild thrombocytopenia and mild increase of inflammatory markers. Serum levels of cobalamin, folic acid, glucose and homocysteine were normal. Autoantibodies panel, including those related to inflammatoy myosites/anti-synthetase syndrome and ANCA were negative. Pulmonary function tests revealed mild restrictive pattern and moderate reduction in DLCO. Six minute walking test documented desaturation on effort.

The new radiological evaluation with CT scan of the chest documented a considerably changed scenario (Fig. 2).

Diffuse mosaic attenuation occurred in both lungs; bilateral consolidations were no longer visible. A fine reticulation associated with mild fibrotic distortion occurred, more pronounced in the right upper lobe and lower lobe. Rare bands were present in the costophrenic angles.

The clinical history was characterized by premature hair graying, macrocytic anemia, mild thrombocytopenia and “lung infiltrates”. Macrocytic anemia need to be separated in megaloblastic anemia and non-megaloblastic anemia.

The causes of megaloblastic anemia were easily excluded.

Myelodysplastic neoplasm is one of the possible causes of non megaloblastic anemia. It manifests with macrocytosis associated to one or more lineage cytopenia.

In this case, peripheral blood smear documenting atypical neutrophils (Fig. 3a), thrombocytopenia and macrocytic anemia suggested a diagnosis of myelodysplastic neoplasm. The definite diagnosis of myelodysplastic neoplasm with increased blasts (blasts in bone marrow aspirate=8-10%) was eventually confirmed by bone marrow aspirate and biopsy (Fig. 3b).

Subsequently the patient was submitted to a bronchoscopy under general anesthesia. A bronchoalveolar lavage (BAL) was carried out in the middle lobe and transbronchial lung cryobiopsies were retrieved from the lateral and posterior segments of the right lower lobe.

BAL

BAL cytological profile was normal and microbiological investigations, including DNA viruses such as cytomegalovirus, Epstein Barr virus, HHV6 and HHV 8 resulted negative.

Lung specimens showed a fibrosing process mainly interstitial (non specific interstitial pneumonia, fibrosing) associated to proliferative bronchiolitis (granulation tissue in the lumen of terminal bronchioles). CD61 monoclonal antibodies depicted scattered interstitial megacaryocytes and intravascular myeloperoxidase positive cells were also detectable in small pulmonary arteries and interstitial capillaries (Fig. 4 a-c).

Diagnosis

The multidisciplinary team agreed with the following diagnosis:

Fibrosing interstitial pneumonia (NSIP-like) associated to proliferative bronchiolitis and increased myeloblasts and megacaryocytes in the intraparenchymal lung structures in a patient with myelodysplastic neoplasm with increased blasts.

The early hair graying in this clinical and morphological context suggests the presence of an underlying telomeropathy.

In the recent WHO classification [WHO classification of tumors Editorial Board. Haematolymphoid tumors. Lyone (France) 2024] the term “myelodysplastic neoplasm” (MDS) was introduced to replace “myelodysplastic syndrome”, underscoring the neoplastic nature of these diseases and harmonizing the terminology with that of myeloproliferative neoplasm (MPN). Patients with MDS have a median age of 77 years at diagnosis, and < 10% are younger than 50 years of age. Cytopenia in at least one haematopoietic lineage is required for a diagnosis of MDS. Dysplasia in one or more myeloid lineages is its morphological hallmark. In this edition of the WHO classification of haematolymphoid tumors, MDS entities are grouped into two families: (1) those with defining genetic abnormalities and (2) those that are morphologically defined. MDS may be part of the spectrum of telomeropathies or associated to GATA2 deficiency. Systemic inflammatory and autoimmune diseases and myelodysplastic syndromes have been linked in case reports and in larger case series. Recently these links have been observed also in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. The prognosis of MDS is poor. Patients with increased blasts have even a poorer prognosis and a higher risk to develop acute myeloid leukemia (Fig. 4d).

Parenchymal lung involvement is part of the clinical spectrum of myelodysplasia associated to telomeropathies, GATA2 deficiency and autoinflammatory/autoimmune disorders and also in “primary” MDS. In the case here reported the final diagnosis is still pending waiting for genetic tests: however the clinical context suggests as the more likely hypothesis a telomeropathy.

Take home messages

MSD DEFINITION

1. persistent cytopenia in one or more peripheral-blood cell lineages
2. morphologic dysplasia (≥10% dysplastic cells) in one or more bone marrow cell lineages;
3. MDS may be part of the spectrum of telomeropathies, GATA2 deficiency or VEXAS syndrome.

RADIOLOGIC SIGNS OF LUNG INVOLVEMENT IN:

Figure e tabelle

Figure 1.(a) Coarse nodularity, perilobular pattern and focal subpleural consolidation ( ). (b-f) Multiple subpleural, rounded consolidations without air bronchogram. (f) Consolidations associated with mild halo sign ( )

Figure 2.(a) Fine reticulation associated with mild fibrotic distortion ); (b-f) Diffuse mosaic attenuation ().

Figure 3.(a) Atypical neutrophils in peripheral blood smear; (b) blasts in bone marrow aspirate.

Figure 4.(a) TBLCB: thickened alveolar septa for deposition of collagen; type II pneumocytes hyperplasia; alveolar spaces contain scattered macrophages (H&E, x 15); (b) TBLCB: a terminal bronchiole shows the lumen almost completely obstructed by a polyp of granulation tissue (proliferative bronchiolitis) (H&E, x 10); (c) TBLCB: a small branch of the pulmonary artery (in the centrilobular zone) shows myeloid cells inside the lumen (Myeoloperoxidase stain, x 10); (d) TREPHINE BONE MARROW BIOPSY: at low power the bone marrow is hypercellular, indicating ineffective hematopoiesis (H&E, x 2)

Riferimenti bibliografici

1. Bejar R, Steensma DP. Williams Hematology. McGraw Hill: New York; 2021.
2. Bixio R, Bindoli S, Morciano A. The role of 18FDG-PET imaging in VEXAS syndrome: a multicentric case series and a systematic review of the literature. Intern Emerg Med. 2024. DOI
3. Borie R, Debray MP, Guedon AF. Pluroparenchymal manifestations of vacuoles E1 enzyme, X linked, autoinflammatory, somatic syndrome. Chest. 2023; 163:575-585. DOI
4. Gurnari C, Pagliuca S, Durkin L. Vacuolization of hematopoietic precursors: an enigma with multiple etiologies. Blood. 2021; 137:3685-3689. DOI
5. Hochman MJ, DeZern AE. Myelodysplastic syndrome and autoimmune disorders: two sides of the same coin?. Lancet Haematol. 2022; 9:e523-e534. DOI
6. Iannone C, Pellico MR, Campochiaro C. The heterogeneity of lung involvement in vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome: a case of hypersensitivity pneumonitis-like pattern. Reumatismo. 2024;76. DOI
7. Marciano BE, Olivier KN, Folio LR. Pulmonary manifestations of GATA2 deficiency. Chest. 2021; 160:1350-1359. DOI
8. Means RF, Glader B. Wintrobe’s Clinical Hematology. Lippincott Williams &amp; Wilkins: Philadelphia; 2014.