Lethal midline granuloma is a rare, aggressive Non-Hodgkin lymphoma of the head and neck. Most cases are of natural killer (NK)/T-cell origin and typically feature the extensive destruction of the nasal structures and nasopharynx with possible dissemination to the skin, soft tissues, gastrointestinal tract, and testes.
Lethal midline granuloma, also known as polymorphic reticulosis or malignant midline reticulosis , is an aggressive Non-Hodgkin lymphoma of the head and neck that arises in the sinonasal structures and nasopharynx. This progressive disease manifests as a necrotizing, destructive midfacial lesion with the erosion of the nasal bone, cartilage, and soft tissue, as well as perforation of the nasal septum  . The vast majority of cases originate from NK/T cell lineage while some emerge from B-cell or peripheral T-cell lineage  . Advanced disease is characterized by involvement of extranodal sites such as the skin, soft tissues, gastrointestinal tract, and testes  .
This lymphoma has a predilection for males and develops approximately in the fourth decade . Symptomology includes constitutional symptoms such as weight loss, fatigue, fever, and night sweats. Patients typically present with nasal pain, obstruction, nasal stuffiness, epistaxis, and possibly purulent rhinorrhea. Facial swelling and pain are also common. Moreover, affected individuals experience dysphagia, odynophagia, hoarseness, trismus, and velopharyngeal dysfunction. Other features include impaired vision and hearing, diplopia, orbital swelling, conjunctivitis, otalgia, and refractory sinusitis. Patients with lung involvement exhibit cough, dyspnea, and difficulty with breathing while those with gastrointestinal (GI) metastasis report early satiety, a feeling of fullness, and possibly evidence of perforation and bleeding.
Upon observation, key findings include facial swelling and erythema. Close inspection may reveal ulceration of the skin, palate, tonsil, and other structures. Additionally, there are likely nasal, orbital, and neck masses. A neurologic exam is necessary for proptosis and cranial neuropathies. Finally, disseminated disease features may include abdominal mass, hepatosplenomegaly, and testicular mass.
Entire Body System
Nasal complaints and fever were frequent manifestation, and physical findings showed necrotic, granulomatous lesions in the nasal cavity in all cases. The survival ranged from 4 to 24 months, giving a mean value of 13 months. [ncbi.nlm.nih.gov]
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[…] often presents with nasal obstruction and/or destruction of adjacent structures May extend into sinuses but does not primarily involve them Marrow and nodes involved only if disseminated Other sites Skin, soft tissue, GI tract, testis May have fever, malaise [surgpathcriteria.stanford.edu]
Other symptoms include fever, malaise, weight loss, a skin lesion like systemic lupus erythematosus (40% of patients), and central nervous system symptoms, including ataxia, mental confusion, and seizures. [headnecksurgery.wordpress.com]
Thirty-five to forty-five percent of patients present with a history of malaise, fever, night sweats, and/or weight loss. [en.wikipedia.org]
- Nasal Ulcer
Oral or nasal ulcer with conjunctivitis may also occur. Perforation of the nasal septum with mutilation of the surrounding tissues eventually occurs.[ 6 ] This entity is associated with Epstein Barr virus. [ncbi.nlm.nih.gov]
Oral or nasal ulcer with conjunctivitis may also occur, and perforation of the nasal septum with mutilation of the surrounding tissues eventually occurs . [ejo.eg.net]
There was no history of epistaxis, anosmia, post nasal drip, oral bleed or cough. Right sided cervical and submandibular lymphadenopathy was observed. [ncbi.nlm.nih.gov]
- Nasal Pain
Patients typically present with nasal pain, obstruction, nasal stuffiness, epistaxis, and possibly purulent rhinorrhea. Facial swelling and pain are also common. [symptoma.com]
- Saddle Nose
Saddle-nose deformity and cauliflower ear are frequent complications. Laryngeal involvement is rare. Presenting symptoms include hoarseness, dyspnea, and rarely hemoptysis. [headnecksurgery.wordpress.com]
Jaw & Teeth
Face, Head & Neck
- Facial Pain
With disease progression, facial pain and destructive sinonasal lesions may ensue. [ajnr.org]
- Facial Edema
Coronal (left) and axial (right) CT scans of the sinus reveal severe pansinusitis with abnormal nasopharyngeal thickening, right facial edema and right temporal bone opacification. [emedicine.medscape.com]
A patient presenting with the above clinical picture should raise suspicion for lethal midline granuloma or other similar diseases. The assessment consists of the patient and family history, a thorough physical exam, and the appropriate studies.
Patients should be evaluated with a complete blood count (CBC) and a complete metabolic panel (CMP) that includes renal and liver function tests and measurement of calcium and uric acid. The results may be notable for anemia, lymphocytopenia, and elevated lactic dehydrogenase (LDH). Very importantly, Epstein-Barr virus (EBV) titers must be obtained.
To clarify the severity and staging of the disease, comprehensive imaging must be performed. Patients should be evaluated with computed tomography (CT) scan of the neck, chest, abdomen, and pelvis. Specifically, CT of the neck and magnetic resonance imaging (MRI) of the head provide crucial information regarding intracranial extension as well as skull base invasion . Other useful modalities include flexible nasopharyngoscopy and direct laryngoscopy.
Biopsy of the primary lesion is a pertinent component of the workup. Numerous samples should be obtained since extensive necrosis is often present. The biopsy may be repeated if the tissue specimens are inadequate. Additionally, disseminated cases may warrant bone marrow biopsy.
Immunohistochemical analysis of the involved tissue reveals an immunophenotypic profile characteristic for positive markers such as CD2, cytoplasmic CD56, and cytoplasmic CD3 epsilon, but negative for surface CD3/Leu4  . Moreover, nearly all cases demonstrate an association with Epstein-Barr virus  . Furthermore, the histological findings include angiocentric patterns with angiodestruction  with lymphoid infiltrate .
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