Case Report: Clinical and Pathological Findings of Tuberculous Gumma: A Case Report and Literature Review

ABSTRACT.

Tuberculous gumma (TG) is a rare type of cutaneous tuberculosis thought to occur as a result of the hematogenous spread of Mycobacterium tuberculosis, which is more common in immunosuppressed individuals. An 8-year-old boy presented with a 2-month history of multiple indolent enlarging ulcerated nodules on his left upper extremity. He had a past medical history of bacille Calmette–Guerin vaccine induced lupus vulgaris. Skin biopsy of the nodules showed granulomas and neutrophil-dominated purulent inflammation. Ziehl–Neelsen staining was negative, and the cultures were positive for M. tuberculosis. Furthermore, the M. tuberculosis complex was identified using metagenomic next-generation sequencing. Standard antitubercular therapy was started at full doses, and the skin lesions had significantly improved 3 months later. Here we review the literature since 2000 and describe the clinical and pathological features of TG.

INTRODUCTION

Cutaneous tuberculosis (CTB) is a Mycobacterium tuberculosis infection that accounts for 1% to 2% of all extrapulmonary manifestations.¹ Despite its rarity and presence in less than 1% of European dermatology clinics, the incidence of CTB has increased.² The clinical manifestations of CTB are diverse and not fully understood.¹ Tuberculous gumma (TG) is a rare form of CTB characterized by the hematogenous spread of Mycobacterium tuberculosis.³ Patients typically present with slowly growing cold nodules and abscesses on the extremities, with pathological features of tuberculous granulomas and caseous necrosis.⁴ Various CTBs have been reported after receiving the bacille Calmette–Guerin (BCG) vaccine.⁵ Here, we describe a case of multiple TG after trauma in a malnourished boy with a past medical history of BCG vaccine–induced lupus vulgaris. Because of the rarity of TG, most of the previous related literature includes case reports, but its clinical features and pathological changes of TG are heterogeneous. This article also reviews the literature on TG to characterize its clinicopathological features.

CASE REPORT

The patient was an 8-year-old malnourished boy with a weight and height of 16 kg and 92 cm, respectively (both below the third percentile). He had sustained a traumatic injury to his left upper extremity 2 months earlier and since then had recurrent multiple nodules at the site of the injury. The lesion started on the anterior surface of the left upper extremity where the lesion was firm and cold, softened into an abscess, and later ruptured into an ulcer. The abscesses gradually increased in size and number. He had a history of BCG vaccine–induced lupus vulgaris at age 3 years. Physical examination revealed multiple purplish-red tender cold abscesses with ulceration and purulent discharge on the anterior surface of the left upper extremity; the abscesses ranged in size from 0.8 to 1.5 cm (Figure 1A). A red plaque 6 cm in diameter with ulcers and cold abscesses was found on the dorsal aspect (Figure 1B). There were scars on the back of the neck from the previous lupus vulgaris (Figure 1C). There was no superficial lymphadenopathy. Systemic examination was unremarkable. Laboratory tests revealed that the blood M. tuberculosis interferon-γ release assay was positive. A Mantoux test was strongly positive. A computed tomography scan of the chest showed an inflammatory nodule in the left lobe, but no evidence of active lung disease. Routine hematological investigations revealed mild anemia with leukocytosis and elevated levels of procalcitonin and C-reactive protein. Serum immunoglobulin and complement levels were all within normal limits. Serology tests for syphilis and HIV were negative. Sputum, stool, and urine cultures were negative. Bone radiographs showed no lytic lesions. Ultrasound of the whole abdomen was normal. Skin biopsy showed epidermal ulceration, and granulomatous inflammation with predominantly epithelioid cells and multinucleated giant cells (Figure 1D–F). There was a neutrophil-dominated purulent inflammation (Figure 1D). The Ziehl–Neelsen stain was negative, whereas mycobacteria grew in the skin tissue culture. In addition, the M. tuberculosis complex was identified using metagenomic next-generation sequencing. Based on the combination of clinical features and laboratory tests, the patient was diagnosed with multiple TGs. He was started on full-dose anti-tuberculosis (TB) therapy, which included isoniazid, rifampicin, pyrazinamide, and ethambutol. His skin lesions had significantly improved 3 months later.

Figure 1.

(A) Multiple purplish-red tender abscesses on the flexion side of the left upper extremity. (B) A purplish red plaque on the extension side. (C) A scar can be seen on the back of the neck from previous lupus vulgaris. (D) Skin biopsy showed a diffuse purulent inflammation dominated by neutrophils (hematoxylin eosin [HE] ×200). (E) Granulomatous inflammation was apparent in some areas (HE ×200). (F) Epithelioid granulomas under high magnification (HE ×400).

DISCUSSION

The clinical manifestations of CTB are extremely diverse.¹ Exogenous infection (TB chancre, TB verrucosa cutis), endogenous infection, or tuberculids (papulonecrotic tuberculid, lichen scrofulosorum) are the most prevalent classifications for this disease.⁴ Endogenous infections can be contiguous (orificialis TB, scrofuloderma), hematogenous (lupus vulgaris, acute miliary TB, and TG), or lymphatic dissemination (lupus vulgaris). In terms of the number of pathogens on the skin, TB variants can be further divided into multibacillary and paucibacillary forms.⁶ Typical histopathological changes in CTB lesions include tuberculous granulomas surrounded by varying degrees of chronic inflammatory cells, sometimes with central caseous necrosis.⁴ Although AFB staining and skin biopsy culture remain the basis for diagnosis of CTB, new techniques and assays, such as nucleic acid amplification and genotyping, are available for clinicians to improve diagnosis.⁷ Several types of TB, including lupus vulgaris, tuberculous chancre, and primary inoculation TB have been documented in previous literature on CTB after BCG vaccination.^5,8 To the best of our knowledge, there have been no reported cases of multiple TG with a past medical history of BCG vaccine induced lupus vulgaris.

Metastatic tuberculous abscess, also known as TG, is thought to occur as a result of the hematogenous spread of M. tuberculosis in immunocompromised individuals.³ Onset of TG can occur at any age but is more common in malnourished children, immunosuppressed adults, and elderly individuals.⁹ Generally, TG presents as multiple, slowly softening subcutaneous nodules and abscesses that gradually break down to form ulcers with bluish margins, mainly on the extremities.⁴ This condition is usually acquired through previous TB infection of the body.¹⁰ Tuberculosis has also been reported to be the initial feature of disseminated TB infection occurring in the absence of a clear underlying infection.¹⁰

A search of the full texts of the articles in the PubMed database revealed 19 patients with TG since 2000 (Table 1).^11–29 In addition to the current patient population, there were 11 males (55.0%) and nine females (45.0%) with a mean age of 42.9 years (range 5–88 years). The majority of TG cases in our study were found in the extremities, followed by the trunk, which is consistent with the finding of previous reports.⁹ Specifically, of these 20 patients, 18 presented with lesions located on the extremities, nine had lesions on the trunk, and only one had lesions in the retroauricular region. As previously reported, the lungs (eight of 20) are the most common extracutaneous site of TG, followed by the bone (six of 20) and lymph nodes (five of 20), suggesting that a complete workup is often required after the diagnosis of TG to exclude extracutaneous TB involvement. Interestingly, five of the 20 patients in this review had no TB location other than the skin. The diagnosis of such a rare condition may alert clinicians to explore the reasons for this condition. Affecting mostly malnourished children and immunocompromised adults, there have been cases of TG in adults with normal immune function. We analyzed the immune profiles of the patients in the literature and showed that immunosuppressive status (including six patients receiving glucocorticoid therapy and one patient each receiving splenectomy, thymectomy, and lymphoma), malnutrition (three patients), local trauma (two patients), pregnancy (one patient), and history of pulmonary TB (including two patients in the past and four patients in the family history) were possible risk factors for disease progression. Multiple diagnostic strategies, including histology, polymerase chain reaction, and culture, should be used to confirm the diagnosis once it has been established clinically. In this review, the Mantoux test was positive in eight of 12 patients and negative in four patients. MTB-PCR was performed for 10 patients, eight of the patients were positive (eight of 10), and 16 patients were positive on culture (16 of 16), suggesting that culture is the most reliable test.

Table 1.

A review of the literature on tuberculous gumma published since 2000

Case	Sex	Age (years)	Location	Extra Skin Sites	Risk Factors	Etiological Assessment			Histopathology of Skin Biopsy
						Mantoux Test	MTB-PCR Test	Cultures	Granuloma w/ or w/o Necrosis	Main Inflammatory Cells	AFB
111	M	45	Abdomen, extremities	Lung	IST, CT		Skin +	Skin +	w/o	LH	+
212	M	56	Thigh, trunk	None	CT	–	Skin +	Pus +	No clear granulomas	Mixed inflammatory cells	+
313	F	70	Forearm, axilla	Lymph nodes	Splenectomy			Lymph node +	No clear granulomas	LH, eosinophils	–
414	F	45	Limb, groins	Lymph nodes, bone	Family history of pulmonary TB	+	Skin +		w/o	Mixed inflammatory cells	–
515	F	33	Buttock, extremities	Lung, bone	Pregnancy		Skin –	Skin +	w/	Neutrophil-dominated purulent inflammation	–
616	F	5	Neck, extremities	Bone	Malnutrition, family history of pulmonary TB	+			w/	LH	–
717	M	8	Retroauricular, extremities	None	Malnutrition	+			w/
818	M	24	Trunk, extremities,	Lung, bone	None			Pus +
919	M	88	Left wrist	None	CT, history of pulmonary TB, trauma	–	Skin –	Skin +	w/	Mixed inflammatory cells	–
1020	F	15	Extremities	Lymph nodes, bone	Malnutrition		Pus +	Pus +
1121	F	40	Left thigh	Lymph nodes	None	+		Lymph node +
1222	F	77	Left knee	Lung	CT	–	Skin +	Skin +	w/	Epithelioid cells and giant cells	–
1323	M	26	Right thigh	Lymph nodes	None	+
1424	F	62	Abdomen, labia majora	Lung, urinary and digestive tract, muscle	Family history of pulmonary TB, thymectomy, IST, CT			Skin, abscess, sputum, urine, gastric juice+	No clear granulomas w/ necrosis	LH	+
1525	F	45	Forearm, finger	Lung	Family history of pulmonary TB, IST, CT		Skin, sputum, gastric juice +	Skin +	No clear granulomas	LH	+
1626	M	68	Chest	None	History of pulmonary TB		sputum +	Skin +
1727	M	44	Extremities	Lung, bone	Alcohol abuse	+		Sputum, skin +	w/	LH, plasma cells	–
1828	M	72	Forearm, perineum	Liver, spleen	Lymphoma	–		Ulcer specimen +
1929	M	19	Extremities	Lung, bone	None	+		Cultures +*	w/
This case	M	8	Left elbow	None	Malnutrition, trauma	+	Skin NGS +	Skin +	w/o	Neutrophil-dominated purulent inflammation	–

AFB = acid-fast bacilli; CT = corticosteroids therapy; F = female; IST: immunosuppressive therapy; LH = lymphohistiocytes; M = male; MTB = Mycobacterium tuberculosis; NGS = next-generation sequencing; PCR = polymerase chain reaction; TB = tuberculosis; w/ = with; w/o = without.

^* The culture source is not provided in the literature.

The histopathological features of TG have not been fully elucidated; therefore, we retrospectively analyzed the histopathological findings of the patients’ lesions. We found that of the 14 patients who underwent skin biopsy in the review, seven had typical tuberculous granulomas with necrosis, and three had only granulomatous changes without necrosis. In addition, four patients had varying degrees of inflammation without clear granulomas. The mixed inflammatory infiltrate of the dermis was dominated by lymphohistiocytes and included epithelioid cells and plasma cells. Interestingly, two of 14 patients showed neutrophil-dominated septic inflammation, which may be a feature and diagnostic clue that distinguishes TG from other CTBs. Although previous literature considered TG to be a multibacillary form of CTB, our literature review found only four positive (four of 12) but eight negative (eight of 12) patients for acid-fast bacilli stains.⁷ Almost all patients had a good prognosis after anti-TB treatment, and only one patient with renal insufficiency relapsed after the dose of anti-TB drugs were reduced.

In conclusion, we present a patient with multiple TGs with a history of BCG vaccine-induced lupus vulgaris and review the literature. The diagnosis of TG remains challenging. Clinicians need to be vigilant for TG in immunocompromised patients. The clinical manifestations and histopathological changes can provide diagnostic clues, but pathological investigations are often needed to confirm the diagnosis.